Fallot tetralogy

Objective: Chronic heart failure is associated with neurohormonal activation that is not only related to outcome but is also a therapeutic target. We have attempted to demonstrate whether a similar pattern of neurohormonal activation exists in adult congenital heart disease (ACHD) and, if so, whether it relates to disease severity determined by cardiopulmonary exercise testing.

Methods and results: Concentrations of N-terminal pro-atrial natriuretic peptide, N-terminal pro-brain natriuretic peptide (NT-proBNP), endothelin (ET)-1, renin, aldosterone, adrenalin, and noradrenalin were determined in 50 adults (mean age, 27.8 [+ or -] 1.7 years [[+ or -] SEM]; 26 women) with tetralogy of Fallot (TOF) after surgical repair (New York Heart Association functional class 1.1 [+ or -] 0.1). One hundred age- and sex-matched healthy blood donors served as a control group for NT-proBNP determination. Dimensions of ventricles, left ventricular pump function, and estimated right ventricular (RV) systolic pressure were determined by echocardiography. Maximum oxygen uptake ([??][O.sub.2]max) was measured in all patients using spiroergometry. TOF patients had elevated levels of NT-proBNP compared with healthy individuals: NT-proBNP (women: 180 pg/mL vs 43 pg/mL, and men: 147 pg/mL vs 32 pg/mL; p < 0.0001) and ET-1 (2.5 fmol/L vs 0.7 fmol/L). There was a significant correlation of NT-proBNP to dimension and estimated peak systolic pressure of the RV as well as impairment of [??][O.sub.2]max.

Conclusions: RV dysfunction detected by echocardiography and plasma NT-proBNP determination in asymptomatic or minimally symptomatic TOF patients correlates well with their cardiopulmonary exercise capacity. Thus, these simple and noninvasive screening methods can be used additionally to stratify ACHD patients with impaired cardiac function before they become clinically symptomatic.

Key words: cardiopulmonary exercise test; congenital heart disease; natriuretic peptides; right ventricular dysfunction; tetralogy of Fallot

Abbreviations: ACHD = adult congenital heart disease; BNP = brain natriuretic peptide; CI = confidence interval. ET = endothelin; FS = fractional shortening; LV = left ventricle/ventricular; LVed = left ventricular end-diastolic dimension; NT-proANP = N-terminal pro-atrial natriuretic peptide; NT-proBNP = N-terminal pro-brain natriuretic peptide; NYHA = New York Heart Association; PR = pulmonary regurgitation; RBBB = right bundle-branch block; RV = right ventricle/ventricular; RVed = right ventricular end-diastolic dimension; TAP = transannular patch; TIvmax = tricuspid valve regurgitation; TOF = tetralogy of Fallot; [??][O.sub.2]max = maximum oxygen uptake

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The number of patients with adult congenital heart disease (ACHD) is growing, and their follow-up, medical treatment, and/or late complications are increasingly important. The most common cause of cyanotic ACHD worldwide is the tetralogy of Fallot (TOF). (1) Follow-up investigations (1,2) of surgical intervention have documented a favorable long-term outcome in these patients. Despite the very good life expectancy, many patients are faced with multiple residua and sequelae. Residual pulmonary artery stenosis and suboptimal relief of the obstructed fight ventricular (RV) outflow tract lead to a state of chronic pressure overload. Additionally, various degrees of pulmonary regurgitation (PR) may create volume overload and eventual dilation of the RV. (3) Due to the hemodynamic burden, heart failure develops in the long-term as an important determinant of morbidity and mortality. (4)

It is important to establish diagnostic tools and methods that are sensitive enough to detect and evaluate developing heart failure at an early stage in patients after corrective surgery. Clinical examinations, including the subjective New York Heart Association (NYHA) functional classification, allow only a rough impression and general estimation of the current status in asymptomatic or minimally symptomatic patients, but they will not be able to reveal a latent cardiac failure as a rule.

Echocardiography can allow objective criteria in determining pump function of the left ventricle (LV). However, in patients with TOF, the systolic function of the LV usually appears to be normal. In these cases, the RV is affected, so that echocardiography is only of limited value.

Brain natriuretic peptide (BNP) is a well-established marker for diagnosis, prognosis, and risk stratification in patients with congestive heart failure. (5-8) The N-terminal pro-BNP (NT-proBNP) represents the N-terminal fragment of pro-BNP, the precursor of the biologically active BNP. Unlike BNP, NT-proBNP circulates at considerable concentrations in human plasma, is stable at room temperature, can easily be detected, and is quantified by immunoassay. (9,10)

Studies (11-14) in adults with congestive heart failure clearly indicate that blood levels of NT-proBNP and the maximal oxygen uptake ([??][O.sub.2]max) index measured by cardiopulmonary exercise testing can be used for objective assessment of heart failure and risk stratification. Little is known about the role of these variables and their interrelationship with respect to the long-term effects of abnormal RV loading conditions in adult TOF patients > 2 decades after surgical repair. Therefore, the purpose of our present study was to measure various clinical parameters in asymptomatic or minimally symptomatic patients with chronic RV pressure and/or volume overload due to operated-on TOF, to investigate the relationship between these variables and clinical status, and finally to propose an efficient usage of these clinical markers.

MATERIALS AND METHODS

Study Population

We performed a prospectively designed detailed assessment of clinical and neurohormonal variables in 50 adult patients with TOF (26 women and 24 men) > 20 years after surgical repair. Patients were consecutively recruited from the specialized ACHD outpatient clinic of the Georg-August-University of Gottingen between January 2001 and September 2003. All the tests for each patient were carried out on the same day. One hundred age- and sex-matched healthy blood donors served as a control group for NT-proBNP levels.

Exclusion Criteria

Exclusion criteria were symptomatic heart failure, acute infection, chronic lung disease, severe mental retardation, and medication, ie, converting enzyme inhibitors and [beta]-blockers.

Clinical Investigation

In addition to a thorough clinical examination, all patients underwent two-dimensional and M-mode echocardiography via a transthoracic approach (Sonos 2000 Diagnostic Ultrasound System; Hewlett-Packard; Andover, MA) interfaced with a multifrequency transducer. LV end-diastolic dimension (LVed) and RV end-diastolic dimension (RVed) were determined by echocardiography from a short-axis view by M-mode. Fractional shortening (FS) was used as a parameter of systolic pump function of the LV. Velocities of tricuspid valve regurgitation (TIvmax) and antegrade pulmonary valve flow were measured by continuous-wave Doppler echocardiography and served to estimate RV systolic pressure and the gradient in the RV outflow tract. Standard 12-lead ECG was recorded to analyze the cardiac rhythm and to determine the width of the QRS complex.

Exercise Testing

Cardiopulmonary exercise testing was performed in all patients on a bicycle ergometer starting with a workload of 35 W, and increasing by 30 W every 3 min. Subjects maintained a pedaling rate from 45 to 65 revolutions per minute. Oxygen consumption was measured using the breath-by-breath technique (Oxycon Pro; Jaeger; Hoechberg, Germany). Exercise was carried out until each subject reached the [??][O.sub.2]max. During exercise, cardiac status was monitored with standard ECG leads and arterial pressure was measured every 3 min. Heart rate was derived from the ECG.

Neurohormonal Assessment

Peripheral venous blood samples were obtained from all participants after they had rested for at least 15 min before exercise testing. Blood samples were immediately placed on ice and centrifuged at 5,000 revolutions per minute for 10 min. Plasma and serum aliquots were stored at -80 [degrees]C until analysis. N-terminal pro-atrial natriuretic peptide (NT-proANP) and endothelin (ET)-I were determined by enzyme immunoassays. NT-proBNP was measured using immunoassay (Elecsys 2010; Roche Diagnostics; Mannheim, Germany). Aldosterone and active renin were determined by radioimmunoassay. Adrenalin and noradrenalin concentrations were measured using high-performance liquid chromatography with electrochemical detection.

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.

Statistical Analysis

The data were analyzed on a personal computer using the statistical software (Excel 2000; Microsoft; Redmond, WA; and Prism; GraphPad Software; San Diego, CA). All results are reported as mean [+ or -] SEM. Groups were assessed using unpaired Student t test. Normal range is given by the 95% confidence interval (CI) of the mean value. For all analyses, p < 0.05 was considered statistically significant.

RESULTS

Clinical Variables

The clinical and demographic characteristics of the 50 patients included in this study are given in Table 1. Age at operation, current age, and follow-up after operation in both groups (male and female) were similar. Ninety-six percent of male patients and 89% of female patients were classified as NYHA functional class I, and the rest were classified as NYHA functional class II. Sixty-eight percent of male and 57% of female patients underwent palliative procedures before surgical repair (Blalock-Taussig shunt in 16 patients and Waterston-Cooley shunt in 11 patients). Sixty percent of men and 64% of women had a transannular patch (TAP) of the pulmonary valve beside infundibulectomy and ventricular septal defect closure with a Dacron or Teflon patch. (Boston Scientific; Natick, MA). The rest of the patients had no transannular patch (non-TAP). Four male and seven female patients underwent pulmonary valve replacement because of significant PR after initial corrective surgery.

ECG

Ninety-six percent of male and 73% of female patients had right bundle-branch block (RBBB) related to surgical procedure. The mean QRS duration ([+ or -] SEM) in men and women with RBBB was 152 [+ or -] 4 ms and 146 [+ or -] 3 ms, respectively. There was no significant distinction in QRS duration between TAP and non-TAP patients in each group. All patients were in sinus rhythm, but two men and two women required a pacemaker due to third-degree atrioventricular block after corrective repair (Table 1). These patients were excluded from the analysis of QRS duration.

Echocardiography

The LVed and the FS of the LV lay within the normal range (Table 1). In all TOF patients, the RVed, measured in short-axis, was enlarged. Thirty patients had mild PR, 18 patients had moderate PR, and 2 patients had severe PR. In 17 patients with moderate-to-severe PR, the outflow tract reconstruction included a TAP. Seven patients had moderate pulmonary stenosis after corrective surgery. In eight patients, we found moderate tricuspid regurgitation. There was a significant correlation between the RVed and the circulating NT-proBNP (r = 0.45, p < 0.05; Table 2). Due to the TIvmax, the estimated RV systolic pressure was also higher in patients than in normal individuals. There was a significant correlation between TIvmax and NT-proBNP (r = 0.42, p < 0.01; Table 2).

Exercise Variables

Nearly all patients showed an impaired [??][O.sub.2]max during exercise testing by spiroergometry. On the average, male patients reached 24 [+ or -] 1 mL/kg/min (62% of the predicted normal), while female patients reached 22 [+ or -] 1 mL/kg/min (71% of the predicted normal) [Fig 1]. (15) The difference achieved a p value of p = 0.04 (Table 1) with the unpaired t test, which is only borderline significant considering the broad scatter of the normal range provided by Pothoff et al. (15)

[FIGURE 1 OMITTED]

Neurohormone Variables

Because the normal ranges for BNP and [??][O.sub.2]max are gender dependent, we analyzed the data of the female and male patient groups separately. Female control subjects were characterized by higher NT-proBNP (43 [+ or -] 4 pg/mL) than male control subjects (32 [+ or -] 3 pg/mL, p < 0.05). This finding is in accordance with the results of other investigators. (9,16,17) Considering all patients, it was evident that adult patients with repaired TOF had significantly higher circulating levels of NT-proBNP compared to control subjects (Table 3; Fig 2). The TOF patients had also significantly higher ET-1 levels than the healthy subjects (Table 3). This value tended to be higher in patients with shunt palliation than without shunt prior to corrective surgery (2.8 [+ or -] 3.2 fmol/mL vs 1.3 [+ or -] 2.3 fmo]/mL). There was no significant difference with regard to gender. The mean values of NT-proANP, adrenalin, noradrenalin, renin, and aldosterone were found to be within the normal ranges (Table 3).

Table 2 depicts the correlation coefficients between the serum concentration of the neurohormones and the clinical, echocardiographic, ECG, and exercise variables. Only NT-proBNP concentration has sufficient correlations to [??][O.sub.2]max, RVed, and estimated RV pressure derived from the TIvmax. Figure 3 shows that the circulating NT-proBNP in TOF patients is closely and inversely associated with [??][O.sub.2]max levels (r = -63, p < 0.001): the lower the NT-proBNP level, the higher the [??][O.sub.2]max.

[FIGURE 3 OMITTED]

Subgroup Comparison

In order to analyze the effect of the pulmonary insufficiency on neurohumoral status and RV size, we compared the data of 20 patients with moderate-to-severe PR with those from 30 patients with mild PR (Table 4). Compared to the patients with mild PR, individuals with moderate-to-severe PR had significantly larger RVeds (mean, 39 [+ or -] 1.3 vs 34 [+ or -] 1.4 mm), higher RV systolic pressure (TIvmax, 3.1 [+ or -] 0.2 m/s vs 2.5 [+ or -] 0.1 m/s), prolonged QRS duration (151 [+ or -] 4 ms vs 133 [+ or -] 6 ms), and more pronounced elevation of the circulating NT-proBNP (219 [+ or -] 33 pg/mL vs 128 [+ or -] 18 pg/mL). The plasma ET-1 was also higher in patients with moderate-to-severe PR (3.6 [+ or -] 1.1 fmol/mL vs 1.6 [+ or -] 0.5 fmol/mL), but this value did not reach statistical significance because of the small number of patients. The cardiopulmonary capacity of the patients with moderate-to-severe PR was slightly but not significantly lower than the patients with mild PR (Vo2max, 23 [+ or -] 1 mL/kg/min vs 24 [+ or -] 1 mL/kg/min).

DISCUSSION

Most long-term follow-up studies in patients with TOF after cardiac surgery reveal good results of corrective repair. (1,18-21) In Germany, the survival rate 20 years and 30 years after surgical repair is estimated to be 94% and 89%, respectively. (2) However, the success of surgery depends also on the remaining morbidity of the surviving patients. Since the investigated patient group shows residual defects such as pulmonary stenosis, PR, and often tricuspid regurgitation, long-term RV pressure and volume overload may lead to consecutive cardiac failure. (22)

In the present study, we included 50 adults surgically corrected for TOF > 20 years ago during childhood. All had residual volume and/or pressure overload of the RV and showed elevated levels of NT-proBNP and ET-1.

In contrast to previous studies, (3,11,22-24) in which the levels for NT-proBNP and ET-1 were also elevated, we could not find any increase of circulating NT-proANP, adrenalin, noradrenalin, renin, or aldosterone in our collective (Table 3). A possible explanation may be the lack of symptomatic patients (NYHA functional classes III or IV) in our study group. Symptomatic patients in NYHA functional classes III or IV generally show elevated adrenergic, renin, and aldosterone activation. (11) Therefore, significant elevation of NT-proBNP may identify the decreased cardiovascular reserve during an early stage of the disease, when patients are still clinically asymptomatic. Moreover, we find a good inverse correlation between the level of NT-proBNP and V[O.sub.2] max both in male and female TOF patients (Fig 3).

[FIGURE 3 OMITTED]

Numerous studies (23,25) on TOF patients have shown that in most cases, LV function was within the normal range. Thus, it is the known RV pressure and/or volume overload that in these patients may lead to increased NT-proBNP levels. As shown in previous investigations, (23,24,26) there is a close correlation between plasma BNP levels and chronic or acute right heart pressure overload.

It has been shown that plasma ET-1 concentrations are elevated in patients with congenital heart defect with left-to-right shunt. (27) The mean pulmonary arterial pressure seems to be the major trigger for net ET-1 production in patients with congenital heart disease and normal pulmonary vascular resistance. (28) In our study group, we found elevated plasma ET-1 concentration. This value tended to be higher in TOF patients with shunt palliation than in patients without shunt prior to corrective surgery and also higher in patients with moderate-to-severe PR than in patients with mild PR. Probably the altered pulmonary vascular bed, due to hypoperfusion and cyanosis before the palliation or correction, led to reduced pulmonary removal of circulating ET-1. In patients with primary aortopulmonary shunt and patients with severe PR, elevated ET-1 was due to the increased production in pulmonary circulation because of pulmonary pressure overload. (27-29)

Long-term studies (30,31) have demonstrated that PR leads to progressive RV dilatation and, with time, to RV dysfunction. Also, QRS prolongation after repair of TOF reflects abnormal and delayed ventricular depolarization and correlates with the degree of RV dilatation. (32,33) In this study, patients with moderate-to-severe PR had significantly larger RVed, longer QRS duration, and higher plasma NP-proBNP levels compared to those with mild PR. These data are in accordance with previous published reports (4,11,23) and indicate that even in asymptomatic or minimally symptomatic TOF patients, RV dilation leads to increased secretion of NT-pro BNP.

In our cohort, NT-proBNP is the only laboratory parameter that correlates with both V[O.sub.2]max and quantitative data of the RV determined by echocardiography. For geometric reasons, noninvasive measurement of RV function by echocardiography is much more difficult and unreliable compared to the well-established measurements of LV function. Measurements of NT-proBNP levels may compensate for this lack of reliable noninvasive data in terms of the risk assessment of patients with RV failure.

We could also show that elevated NT-proBNP levels in patients with TOF during long-term follow-up after surgical repair correlate not only with RV size but also with cardiopulmonary exercise capacity measured by spiroergometry. We are now able to explain that the impaired V[O.sub.2]max during exercise testing in our patients is caused by heart failure if elevated NT-proBNP levels represent elevated filling pressures of the heart. (8,34) As has been previously shown that NT-proBNP levels can distinguish heart failure from lung diseases in patients presenting with dyspnea, (35,36) we can speculate that the reduced V[O.sub.2]max of our patients is not predominantly caused by lung injury after (in part) multiple cardiac thoracic operations. Thus, patients with markedly reduced V[O.sub.2]max and elevated NT-proBNP are probably more at risk for heart failure and should be monitored carefully.

The "in part" difficult decisions for further cardiac surgery like pulmonary valve replacement, for cardiac interventions like pulmonary artery balloon dilation, or pharmacologic approaches may be made easier by these objectively measurable data. Moreover, determinations of NT-proBNP levels and V[O.sub.2]max during exercise testing may represent good candidates for study end points of clinical trials with the partly competitive therapeutic interventions discussed above.

It is not known whether elevated NT-proBNP levels predict mortality in patients with congenital heart disease after cardiac surgery, as was previously demonstrated in adults with heart failure. (37) We are presently investigating this important question in a prospective trial in 350 adolescents with operated congenital heart disease, and have been able to show that patients with operated-on TOF are more prone to congestive heart failure in the long-term course than patients after correction of simple lesions. (38) Taken together, risk stratification of heart failure in patients with congenital heart disease after cardiac surgery can be improved by measurement of NT-proBNP levels together with spiroergometry data.

Limitations

There are some limitations in our work. We performed a cross-sectional study; thus, our data reflect only the status quo in these patients. Further, longitudinal investigations are required to evaluate the cardiorespiratory and neurohormonal status in ACHD patients to find out whether the alteration of these parameters permits us to predict mortality or not. Assessing the dimension and function of the RV is challenging because of its complex anatomy, especially in patients with operated-on TOF. None of the geometric assumptions used to assess LV function hold true for the RV. Thus, in the clinical setting the estimation of RV dimensions and the assessment of RV function are based often on echocardiography, which allows easily qualitative investigations, whereas quantitative analysis remains limited and frequently difficult to reproduce. To minimize the interobserver variability in our study, all echocardiographs were done by one investigator (K.N.). The invasive hemodynamic evaluation was conducted only in a few patients (n = 4) during the study, so that we used the TIvmax to estimate the RV systolic pressure. Although our data showed normal LV function based on FS, this does not permit drawing conclusion on the overall LV function, as diastolic function has not been determined.

CONCLUSION

In 50 adults with TOF after corrective surgery, the cardiopulmonary capacity (V[O.sub.2]max) and neurohormonal activities were determined, and hemodynamic status was evaluated by two-dimensional echocardiography. The patients showed reduced V[O.sub.2]max, elevated NT-proBNP, and increased RV size and systolic pressure. LV size and pump function were normal. Between V[O.sub.2]max and NT-proBNP, there was a significant inverse correlation. We found also a correlation between RV size, estimated maximal systolic pressure, and NT-proBNP as an indication of latent heart failure. Thus, the determination of these parameters can be used as additional screening methods to stratify TOF patients at risk for impaired cardiac function before they become clinically symptomatic.

[FIGURE 2 OMITTED]

ACKNOWLEDGMENT: We thank our study nurse Barbara Formanek, and Renate Lucyga, Ursula Baumgarten, and Sabine Laurenzano for technical assistance; and Talat Mesud Yelbuz, MD, PhD, for critical reading of the manuscript and suggestions for improvement.

Manuscript received January 10, 2005; revision accepted April 20, 2005.

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Kambiz Norozi, MD; Reiner Buchhorn, MD; Christian Kaiser; Georg Hess, MD; Rolf W. Grunewald, MD; Lutz Binder, MD; and Attain Wessel, MD

* From the Department of Pediatric Cardiology and Intensive Care (Drs. Norozi and Wessel), Medical School Hannover, Hannover; University of Gottingen (Dr. Buchhorn and Mr. Kaiser), Gottingen; Departments of Internal Medicine (Dr. Grunewald) and Clinical Chemistry (Dr. Binder), Georg-August-University, Gottingen; and Roche Diagnostics (Dr. Hess), Mannheim, Germany.

Correspondence to: Kambiz Norozi, MD, Medical School Hanhover, 30625 Hannover, Germany; e-mail: Norozi.kambiz@mhhannover.de

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