Abstract
Background
Exercise capacity and endothelial function are impaired in adults with repaired tetralogy of Fallot (ToF). This may be related to pathophysiological determinants, such as cardiac and endothelial impairment, or to a more sedentary lifestyle. Therefore, we sought to assess if cardiac and endothelial function are associated with exercise capacity in adults with repaired ToF.
Methods
In a case-control study, we compared adults with repaired ToF and controls in terms of exercise workload, peak oxygen consumption (VO2peak) and flow-mediated dilation (FMD). Additionally, we determined associations of natriuretic peptide levels, echocardiographic parameters of size, function and systolic pressure with exercise capacity.
Results
A total of 26 patients (mean age 38 ± 10 years, 46% males) and 10 controls were included. Patients with repaired ToF had reduced VO2peak (25.0 vs. 36.3 ml/kg/min, p < 0.001) and FMD (7.6 vs. 10.8%, p = 0.007) compared to controls. Exercise workload was moderately associated with FMD (r = 0.428, p = 0.029) and right ventricular parameters, while VO2peak was moderately associated with natriuretic peptide levels (r = −0.523, p = 0.006).
Conclusions
Adults with repaired ToF have impaired exercise capacity and endothelial function as compared to healthy controls. Natriuretic peptide levels and FMD are moderately associated with exercise capacity in adults with repaired ToF.
Keywords: Tetralogy of fallot, Exercise testing, Vascular function, Echocardiography, Natriuretic peptides, Physical activity
1. Introduction
Tetralogy of Fallot (ToF) is the most common cyanotic congenital heart defect, occurring in approximately 1 of 3500 births [1]. Despite improved survival to adult life [2,3], impaired cardiac and vascular function, persisting hemodynamic derangements, cardiac autonomic disturbances and sedentary lifestyle [4,5] may result in significant impairments of exercise capacity and quality of life [1,[6], [7], [8]]. Moreover, reduced exercise capacity, together with impaired cardiac and vascular function, has been associated with increased morbidity and mortality of patients after ToF repair [[9], [10], [11], [12], [13]].
Also, vascular structure and function is impaired in patients with repaired ToF. Congenital specifics of the arterial tree with impaired collagen/elastin ratio [14], autonomic cardiovascular dysfunction [5], impaired repolarization [15], cyanosis [16] and sedentary lifestyle [17] have been identified as possible contributors. Flow-mediated dilation (FMD) has emerged as an indicator of endothelial function, an early marker of cardiovascular disease and a predictor of cardiovascular prognosis in non-congenital heart disease [18,19] and Fontan circulation [20]. Endothelial function impairment has been shown in children early after ToF repair [21], whereas its persistence in adults has not been confirmed [22]. Association between FMD and clinically relevant outcomes has not been examined so far in adults after ToF repair.
Possible ramifications of cardiac and endothelial impairments include exercise intolerance in adults with repaired ToF [23]. However, sedentary lifestyle may also be a contributing factor, as adults with congenital heart disease including ToF repair—also due to previously cautious recommendations by healthcare professionals—are less physically active and less engaged to sports compared to healthy peers [17,24,25].
Therefore, we sought to assess endothelial function (FMD), cardiac function (echocardiographic and neurohormonal indices of right ventricular function), self-reported physical activity and exercise capacity, their intercorrelation, and their association with exercise capacity in adults with repaired ToF.
2. Materials and methods
2.1. Participants
This was a case-control study carried out at the Department of Vascular Diseases, Division of Internal Medicine, University Medical Centre Ljubljana, Slovenia. Consecutive patients with repaired ToF, referred for exercise testing were recruited from the national referral Outpatient clinic for adults with congenital heart diseases at the Department of Cardiology, University Medical Centre Ljubljana, Slovenia. Control group was asked to participate in the study if they had neither signs nor symptoms of heart failure and/or coronary artery disease. Those to whom medications were prescribed had had echocardiography performed and demonstrable structural abnormalities were excluded. Beta blockers were prescribed to 2 of them: one for arterial hypertension deemed adrenergic in origin (resting heart rate >90/min) and one for palpitations without evidence of structural or electric cardiac abnormalities after extensive non-invasive work-up.
Patients with repaired ToF had a complete surgical repair of the cardiac defect in the childhood. They were all in the clinical class I according to NYHA classification. Exclusion criteria included known or symptomatic atherosclerotic disease, unstable cardiovascular disease or recent (<3 months prior to inclusion) cardiovascular events, acute illness or recent (<3 months prior to inclusion) non-cardiovascular diseases requiring hospital, emergency or unplanned specialist management, pregnancy, unstable arrhythmias, chronic atrial fibrillation, permanent pacing and intellectual development disorder.
The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the National Medical Ethics Committee of the Republic of Slovenia. Informed consent was obtained from each patient included in the study.
2.2. Endothelial function
The examination was performed in the morning hours. Participants were lying in the supine position at least 10 min before measurements. Aloka Prosound α7 ultrasound machine was used for measuring FMD. Measurements were performed on the right brachial artery; participants were asked not to move at all. The first step was to visualize the artery approximately 5 cm above the antecubital fossa. After having the artery visualized in the horizontal position on the screen, 3 measurements of the arterial diameter were obtained (d1). Next step was inflating the cuff just below the antecubital fossa with the pressure which is 50 mmHg above the systolic blood pressure. Ischemia was maintained for 4.5 min. Sixty seconds after deflation of the cuff, 3 measurements of the arterial diameter were obtained again (d2). FMD was calculated with the following formula:
in which FMD represent flow-mediated dilation, while and represent mean arterial diameters before and after the cuff inflation, respectively.
The same investigator carried out all measurements. To assess the reproducibility of the measurements, 9 subjects were selected randomly. The intraclass correlation coefficient for this group was 0.725, p = 0.009.
2.3. Cardiopulmonary exercise testing (CPET)
Maximal CPET was carried out in a laboratory room between 10 a.m. and 2 p.m. using cycle ergometer Schiller CS-200. Standardized exercise testing protocol consisted of gradual increase in workload by one tenth of maximal estimated workload per minute (on the basis of age, sex and height). As a part of calibration, a spirometric measurement was performed. Participants were ECG monitored during whole CPET and in the cool-down period. Oxygen and carbon dioxide flow were permanently measured during exercise. Anaerobic threshold was defined when ratio between oxygen and carbon dioxide flow was 1. Chronotropic competence was calculated with the formula: HRpeak/(220 - age), in which HRpeak represents peak heart rate during CPET.
Patients with repaired ToF were divided into 2 subgroups according to exercise testing capacity. Subgroup 1 consisted of patients who reached 85% or more of expected peak oxygen consumption (VO2peak) during CPET. Subgroup 2 consisted of patients who did not reach 85% of expected VO2peak. This cut-off of 85% was chosen on the basis of the clinical experience and literature suggestions [26,27].
2.4. Cardiac function
Transthoracic echocardiography was performed using Phillips Epic 7c ultrasound system with 3D transducer (X5-1). Measurements were performed according to current guidelines [28]. Long-axis parasternal view was used for measuring left ventricular end-diastolic diameter, intraventricular septum diameter and left ventricular posterior wall diameter, according to current guidelines. Left ventricle ejection fraction was measured using a biplane method of disks (modified Simpson's rule). A right ventricular diameter at the base, as a measure of right ventricular size, was determined from the 4-chambers view, according to the report of the American Society of Echocardiography [28]. Velocity of the tricuspid annular systolic motion, as an indicator of right ventricular systolic function, was assessed with tissue Doppler using an apical 4-chamber window. Right ventricular systolic pressure was calculated from peak tricuspid regurgitation jet velocity, as described in details in the guidelines. Also, tricuspid regurgitation, pulmonary stenosis, pulmonary regurgitation and aortic regurgitation were examined and semi-quantified according to guidelines [28].
Natriuretic peptide levels, representing neurohormonal parameters of heart failure, were obtained from the serum. The N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was determined with the dedicated immunoassay.
2.5. Self-estimated physical activity level
Self-estimated physical activity level was assessed using the short form of the International Physical Activity Questionnaire (IPAQ). According to authors’ guidelines, metabolic equivalents of task (MET) were calculated, based on frequency, intensity and duration of the physical activity [29].
2.6. Statistical analysis
Data were analyzed using IBM SPSS Statistics for Windows, version 20 (IBM Corp., Armonk, N·Y., USA). Distribution of a variable was assessed with the Shapiro-Wilk test. Data were presented as mean and standard deviation for normally distributed variables, and median and interquartile range for non-normally distributed variables. Due to the small numbers of patients, Mann-Whitney U test was used to determine differences of both normally and non-normally distributed continuous variables. Differences between categorical variables were checked with chi-square test. Spearman's rank correlation coefficient was used to identify possible association among variables. Correlation coefficients in a range of 0.10–0.39 indicated a weak relationship, in a range of 0.40–0.69 indicated a moderate relationship, in a range of 0.70–0.89 indicated a strong relationship, while coefficients >0.90 indicated a very strong relationship [30]. A p value equal to or less than 0.05 was considered statistically significant.
3. Results
A total of 26 patients with repaired ToF and 10 age-matched controls were included (Table 1).
Table 1.
Demographics and clinical data of the participants included in the study.
| ToF |
Control group |
p-value | |||
|---|---|---|---|---|---|
| n = 26 | n = 10 | ||||
| Demographics | |||||
| Age, mean (SD), y | 37.7 | (9.8) | 39.3 | (8.2) | 0.502 |
| Male sex, n (%) | 12 | (46.1) | 6 | (60.0) | 0.710 |
|
BMI, mean (SD), kg/m2 |
24.9 |
(5.3) |
23.7 |
(2.5) |
0.646 |
| Clinical data | |||||
| Systolic pressure, median (Q1-Q3), mmHg | 115 | (105–130) | 120 | (114–126) | 0.720 |
| Diastolic pressure, median (Q1-Q3), mmHg | 75 | (70–80) | 80 | (70–80) | 0.534 |
|
Resting HR, mean (SD), min−1 |
72.9 |
(10.2) |
75.1 |
(12.6) |
0.874 |
| Drugs | |||||
| Beta blockers, n (%) | 6 | (23.1) | 2 | (20.0) | 1.000 |
| ACEi/ARB, n (%) | 4 | (15.4) | 0 | (0.0) | 0.559 |
|
Statins, n (%) |
2 |
(7.7) |
0 |
(0.0) |
1.000 |
| Vascular function | |||||
|
FMD, mean (SD), % |
7.6 |
(3.3) |
10.8 |
(2.3) |
0.007 |
| Cardiopulmonary exercise testing | |||||
| Maximal workload, mean (SD), W | 146.5 | (60.8) | 249.7 | (99.7) | 0.001 |
| Percentage of predicted workload, mean (SD), % | 89.2 | (24.1) | 139.6 | (44.9) | 0.002 |
| VO2peak, mean (SD), ml/kg/min | 25.0 | (6.6) | 36.3 | (6.5) | <0.001 |
| Percentage of predicted VO2peak, mean (SD), % | 79.9 | (18.7) | 110.3 | (26.0) | 0.001 |
| VO2 at AT, mean (SD), ml/kg/min | 20.3 | (5.2) | 27.7 | (7.1) | 0.004 |
|
VE/VCO2 slope, mean (SD) |
24.5 |
(4.4) |
22.0 |
(2.6) |
0.094 |
| Biomarkers | |||||
| NT-proBNP, median (Q1-Q3), ng/L | 181 | (89–338) | N/A | N/A | |
ACEi/ARB – angiotensin converting enzyme inhibitors/angiotensin receptor blockers; AT – anaerobic threshold; BMI – body mass index; FMD – flow-mediated dilation; HR – heart rate; NT-proBNP – N-terminal prohormone B-type natriuretic peptide; Q1-Q3 – interquartile range; SD – standard deviation;; ToF – tetralogy of Fallot; VE/VCO2 slope - minute ventilation/carbon dioxide production slope; VO2peak – peak oxygen consumption.
Patients with repaired ToF had significantly reduced exercise workload (146.5 vs. 249.7 W, p = 0.001), lower percentage of the predicted workload (89.2 vs. 139.6%, p = 0.002), lower VO2peak level (25.0 vs. 36.3 ml/kg/min, p < 0.001), and oxygen consumption at anaerobic threshold (20.3 vs. 27.7 ml/kg/min, p = 0.004) compared to healthy controls. Vascular function, determined with FMD, was also significantly decreased, as compared to healthy controls (7.6 vs. 10.8%, p = 0.007).
Six out of 26 patients with repaired ToF were taking beta blockers as a heart failure therapy (n = 2), due to ventricular arrhythmias (n = 2), secondary prevention after myocardial infarction (n = 1) and an antihypertensive therapy (n = 1); four out of 26 were taking ACEi/ARB as a part of antihypertensive therapy (n = 2), heart failure (n = 1) and secondary prevention after myocardial infarction (n = 1). All the patients successfully completed CPET, with neither ischemic signs or symptoms nor ECG changes. One patient experienced presyncope after exercise testing requiring observation at the emergency department, and was adscribed to pronounced peripheral vasodilation in the immediate post-exercise period.
Patients with repaired ToF were divided into 2 subgroups according to exercise testing capacity. Subgroup 1 consisted of patients who reached 85% or more of expected (VO2peak) during CPET. Subgroup 2 consisted of patients who did not reach 85% of expected VO2peak. Table 2 shows differences between subgroups of patients with repaired ToF.
Table 2.
Comparison of the clinical data between two examined subgroups of patients with repaired tetralogy of Fallot.
| All ToF patients (n = 26) | Subgroup 1 (VO2 peak ≥85% predicted)(n = 10) | Subgroup 2 (VO2 peak <85 (n = 16) | p value | ||||
|---|---|---|---|---|---|---|---|
| Clinical data | |||||||
| Age, mean (SD), y | 37.7 | (9.8) | 41.6 | (10.4) | 35.3 | (8.9) | 0.119 |
| Male sex, n (%) | 12 | (46.1) | 7 | (70.0) | 5 | (31.3) | 0.105 |
| BMI, mean (SD), kg/m2 | 24.9 | (5.3) | 27.0 | (5.1) | 23.6 | (5.2) | 0.155 |
| Time after repair, mean (SD), y | 32.4 | (8.3) | 37.7 | (8.5) | 32.3 | (7.8) | 0.140 |
| Age at repair, median (Q1-Q3), months | 30.0 | (22.5–55.5) | 36.0 | (27.0–61.5) | 24.0 | (18.0–52.5) | 0.244 |
| Number of procedures, 1/2/3 or more, n | 10/12/4 | 6/3/1 | 4/9/3 | 0.203 | |||
| Blalock-Taussig shunt, n (left/right) | 9 | (6/3) | 3 | (2/1) | 6 | (4/2) | 1.000 |
| Residual VSD, n (%) | 4 | (15.4) | 0 | (0) | 4 | (25.0) | 0.136 |
| Pacemaker, n (%) | 2 | (7.6) | 0 | (0) | 2 | (12.5) | 0.508 |
|
QRS duration, median (Q1-Q3), ms |
160 |
(152–171) |
159 |
(156–163) |
165 |
(150–176) |
0.874 |
| Cardiopulmonary exercise testing | |||||||
| Peak workload, mean (SD), W | 146.5 | (60.8) | 200.7 | (55.8) | 112.6 | (33.3) | <0.001 |
| VO2peak, mean (SD), ml/kg/min | 25.0 | (6.6) | 30.7 | (5.5) | 21.4 | (4.3) | 0.001 |
| VO2 at AT, mean (SD), ml/kg/min | 20.3 | (5.2) | 25.0 | (4.1) | 17.3 | (3.3) | <0.001 |
| VE/VCO2 slope, mean (SD) | 24.5 | (4.4) | 23.9 | (4.4) | 24.9 | (4.5) | 0.493 |
| Resting HR, mean (SD), min−1 | 72.9 | (10.2) | 71.7 | (6.4) | 73.6 | (12.1) | 0.833 |
| Resting SBP, median (Q1-Q3), mmHg | 115 | (105–130) | 125 | (109–133) | 110 | (105–128) | 0.141 |
| Resting DBP, median (Q1-Q3), mmHg | 75 | (70–80) | 80 | (68–85) | 70 | (70–80) | 0.202 |
| HRpeak, median (Q1-Q3), min−1 | 162 | (146–174) | 161 | (153–179) | 162 | (143–170) | 0.292 |
| SBPpeak, median (Q1-Q3), mmHg | 170 | (158–200) | 205 | (189–220) | 160 | (145–170) | <0.001 |
| DBPpeak, median (Q1-Q3), mmHg | 80 | (79–85) | 88 | (80–100) | 80 | (71–80) | 0.005 |
| HRpeak∗SBPpeak, mean (SD), mmHg/min | 27348 | (6786) | 33477 | (4554) | 23518 | (4861) | <0.001 |
|
Chronotropic competence, mean (SD), % |
85.4 |
(13.1) |
92.3 |
(7.0) |
81.8 |
(14.4) |
0.014 |
| Vascular function | |||||||
|
FMD, mean (SD), % |
7.6 |
(3.3) |
9.0 |
(2.9) |
6.7 |
(3.4) |
0.042 |
| Echocardiography | |||||||
| LV EDd, mean (SD), cm | 4.7 | (0.5) | 4.8 | (0.5) | 4.6 | (0.4) | 0.186 |
| IVSd, mean (SD), cm | 0.9 | (0.2) | 1.0 | (0.2) | 0.9 | (0.2) | 0.404 |
| LV PWd, mean (SD), cm | 0.9 | (0.2) | 1.0 | (0.1) | 0.9 | (0.2) | 0.126 |
| EF LV, mean (SD), % | 62.2 | (8.3) | 59.2 | (5.9) | 64.2 | (9.2) | 0.154 |
| RV Db, mean (SD), cm | 4.7 | (0.7) | 4.4 | (0.5) | 4.8 | (0.8) | 0.245 |
| RV S′, mean (SD), cm/s | 11.2 | (2.3) | 12.3 | (2.0) | 10.5 | (2.2) | 0.068 |
| RV SP, mean (SD), mmHg | 36.0 | (10.6) | 32.3 | (9.0) | 38.3 | (11.2) | 0.162 |
| LV EDd/RV Dd, mean (SD) | 1.0 | (0.2) | 1.1 | (0.2) | 0.9 | (0.2) | 0.061 |
| Tricuspid regurgitation, no/mild/moderate/severe, n | 0/21/4/1 | 0/8/2/0 | 0/13/2/1 | 0.653 | |||
| Residual pulmonary stenosis, no/mild/moderate/severe, n | 11/11/4/0 | 6/4/0/0 | 5/7/4/0 | 0.155 | |||
| Pulmonary regurgitation, no/mild/moderate/severe, n | 7/8/9/2 | 2/5/3/0 | 5/3/6/2 | 0.309 | |||
|
Aortic regurgitation, no/mild/moderate/severe, n |
20/6/0/0 |
9/1/0/0 |
11/5/0/0 |
0.211 |
|||
| Biomarkers | |||||||
|
NT-proBNP, median (Q1-Q3), ng/L |
180.9 |
(88.9–337.9) |
87.3 |
(35.9–171.5) |
227.7 |
(118.3–459.3) |
0.007 |
| Physical activity level | |||||||
| IPAQ score, median (Q1-Q3), Total MET min/week | 2263 | (1370–4089) | 2930 | (1751–5547) | 1844 | (1350–3202) | 0.170 |
AT – anaerobic threshold; BMI – body mass index; DBP – diastolic blood pressure; FMD – flow-mediated dilation; HR – heart rate; IPAQ – self-estimated physical activity score; IVSd – intraventricular septum diameter; LV EDd – left ventricular end-diastolic diameter; LV PWd – left ventricle posterior wall diameter; MET – metabolic equivalent of task; NT-proBNP – N-terminal prohormone B-type natriuretic peptide; Q1-Q3 – interquartile range; RV Db – right ventricle base diameter; RV S’ - tissue Doppler-derived right ventricular systolic excursion velocity; RV SP – right ventricular systolic pressure; SBP – systolic blood pressure; SD – standard deviation; VE/VCO2 slope - minute ventilation/carbon dioxide production slope; VO2peak – peak oxygen consumption; VSD – ventricular septal defect.
As it is shown in Table 2, patients with impaired exercise capacity had expectedly lower values of exercise testing parameters and FMD, and higher NT-proBNP levels, as compared to those who had reached at least 85% of expected exercise capacity. There were no significant differences between subgroups in terms of echocardiographic parameters (Table 2). Also, differences between two subgroups in terms of self-estimated physical activity level were not significant.
FMD, as a marker of endothelial dysfunction, was moderately, but significantly correlated with exercise workload (r = 0.428, p = 0.029) (Fig. 1). Associations of NT-proBNP levels and both exercise capacity and exercise workload were moderate and significant (r = −0.523, p = 0.006 and r = −0.557, p = 0.003, respectively). Right ventricular systolic function, and right ventricular systolic pressure were moderately associated with exercise workload (r = 0.404, p = 0.040 and r = −0.411, p = 0.037, respectively) (Fig. 2a). Right ventricular base diameter, as a parameter of right ventricular size, was associated with neither exercise workload nor exercise capacity. However, the association between ratio left ventricle end-diastolic diameter/right ventricular base diameter, and exercise workload was weak to moderate (r = 0.399, p = 0.043).
Fig. 1.
Association between exercise workload and flow-mediated dilation (FMD) in patients with repaired tetralogy of Fallot.
Fig. 2.
Associations of echocardiographic parameters with (a) exercise workload, and (b) natriuretic peptide levels (NT-proBNP) (RV Db – right ventricular base diameter; RV S’ - tricuspid annular systolic motion; RV SP – right ventricular systolic function).
Furthermore, natriuretic peptide levels were moderately correlated with echocardiographic parameters of right ventricular size and systolic pressure (r = 0.635, p < 0.001 and r = 0.441, p = 0.024) (Fig. 2b), while association with right ventricular systolic function was weak and showed a trend towards statistical significance (r = −0.382, p = 0.054).
4. Discussion
Endothelial function (FMD) and exercise capacity are impaired in adults after ToF repair as compared to healthy age-matched controls. Moreover, endothelial function impairment and exercise capacity are moderately associated.
Previous studies have shown impaired exercise capacity and suggested impaired endothelial function in adults after ToF repair. Trojnarska et al. reported exercise capacity reduction in the range of two-thirds of expected capacity [8]. Similarly, our results have shown that exercise capacity is reduced to 80% of expected achievements with low symptom burden (all our participants were in NYHA class I) and age (38 years) possibly explaining the difference in achieved capacity. In terms of impaired endothelial function, available evidence is less consistent. Studies with cyanotic adults, including subsets of patients with repaired ToF [8,31] have shown impaired FMD. Also in children early after ToF repair, FMD is significantly impaired [21]. Conversely, studies in adults with cyanotic congenital heart disease [32] and repaired ToF only [22] have not demonstrated persistent peripheral endothelial dysfunction, although a smaller number of participants may provide some explanation. In fact, pathophysiologic substrate in terms of derangements in cardiac-vascular hemodynamic coupling, post-surgery sequelae and disarranged vascular architecture with impaired collagen/elastin ratio in large arteries [14] may predispose adults after ToF repair to peripheral vascular impairments. We may speculate that the impaired collagen/elastin ratio may be present in brachial arteries as well, as their walls are also consisted of collagen and elastin fibres [33]. In addition, peripheral endothelial dysfunction may be related to postoperative hemodynamic abnormalities without structural changes in the peripheral vasculature (e.g. changes in transmural pressure or oxidative stress), as stated in a study of de Groot and colleagues [21]. Finally, the Blalock-Taussig shunt in childhood may additionally affect arterial flow in brachial and lower arm arteries on the operated side [34].
A further, novel finding is the association between FMD and exercise capacity. Although endothelial dysfunction has been moderately associated with impaired exercise capacity in patients with coronary artery disease [35] and heart failure [36], such association in adults with repaired ToF has not been reported to date. Adequate vasodilatation is a pivotal response to exercise; impaired vascular function may therefore likely thwart appropriate exercise capacity. In addition to endothelial function, markers of cardiac dysfunction—namely echocardiographic indices of systemic (right) ventricular performance and NT-proBNP levels [37]—were also moderately associated with exercise capacity of our study participants. This is in line with most, but not all, reports on the association between exercise capacity and ventricular function in imaging [[38], [39], [40]] and neurohumoral studies [8,23,26].
An important question is whether exercise capacity is hampered by pathophysiologic vascular and cardiac derangements, or is it rather a consequence of an interplaying confounder, affecting both vascular function and exercise capacity, such as sedentary lifestyle. Exercise training improves endothelial function [41]; therefore, decreased FMD in adults with repaired ToF likely reflects physical inactivity rather than causing it. This is an important suggestion of the importance of regular physical activity in patients after ToF repair. It seems that physical activity with all its aspects, such as shear stress increase, pro- and antioxidative cytokines modulation and control of cardiovascular risk factors, is beneficial for both healthy individuals and patients with cardiovascular disease [42], especially for adults with congenital heart disease [43].
Our study provides novel insight into the complex association between cardiac and endothelial function, exercise capacity and physical activity in adults after ToF repair. However, we identified some limitations. Firstly, a relatively small sample size (that affects statistical analyses, especially regression) and case-control design of the study require caution, but reflect a relatively low prevalence of adults with repaired ToF. Secondly, controls were matched for age, but were not adjusted for other differences, which may have influenced our results. Thirdly, cardiac function was estimated echocardiographically, whereas advanced imaging methods (such as with magnetic resonance) may provide better appreciation of the right ventricular function and its association with exercise capacity. Fourthly, all FMD acquisitions, including 3 patients with right Blalock-Taussig shunt, were performed on the right hand, which might have affected results to some degree. Nonetheless, our findings improve understanding of complex pathophysiologic phenomena in a population of patients after ToF that has only recently started reaching middle age and require better appreciation of possible cardiovascular risks embedded in its specific disease trajectory.
In conclusion, exercise capacity and endothelial function are impaired in adults after ToF repair. Both endothelial (as determined by FMD) and cardiac dysfunction (as determined by echocardiography and NT-proBNP levels) are moderately associated with exercise capacity.
Conflict of interest
The authors declare that they have no conflict of interest.
Acknowledgements
We thank all the participants in this study. We specially thank all nurses and administrators from The Center of Preventive Cardiology, Department of Vascular Diseases, Mojca Bervar, MD and staff from The Non-invasive Cardiac Laboratory, Department of Cardiology, and Mojca Božič-Mijovski, PhD and staff from The Laboratory for Haemostasis and Atherothrombosis, Department of Vascular Diseases, for generously helping us in this research.
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