Introduction
Cardiovascular diseases are a major public health problem and leading cause of death worldwide [
1]. In adults, cardiovascular exercise tests are used as a screening tool to identify patients at increased risks of cardiovascular diseases, even when clinical symptoms are not yet present [
2]. In pediatric clinical populations, cardiac exercise testing is mostly used in children with a known cardiac abnormality to evaluate the severity of the condition, effects of treatment and prognosis [
3‐
5]. During exercise, the response of the circulatory system is designed to match the higher oxygen requirements in the exercising muscles by raising heart rate, heart contractility and blood pressure [
6]. In both adult and pediatric populations with cardiac abnormalities and cardiovascular diseases, an abnormal response of the cardiovascular system to exercise is associated with poorer cardiovascular health outcomes and overall reduced quality of life [
7‐
9].
Accumulating evidence suggests that cardiovascular diseases might originate from early life onwards [
10]. Early life exposures during pregnancy and childhood may be associated with persistent cardiac structural and functional developmental adaptations, predisposing to increased risks of cardiovascular dysfunction and diseases in later life [
11‐
13]. Recent evidence from small pediatric studies suggests that cardiovascular exercise testing may provide important information on cardiovascular health in non-diseased pediatric populations, which enables detection of subtle cardiovascular dysfunction not yet present in rest [
14,
15]. The application of cardiovascular exercise tests in longitudinal birth cohort studies may serve as a valuable tool to reveal subtle cardiovascular developmental adaptations in response to early life exposures, and to better identify children who are at a higher risk of cardiovascular diseases and mortality in later life. CMR during exercise provides superior high resolution image quality and can produce 3D images of all the cardiac chambers. Several small studies have used CMR to obtain more detailed insight into cardiac adaptations to exercise and showed differences in cardiac response to exercise in diseased and non-diseased populations [
16‐
18]. Combined with CMR, Isometric handgrip exercise is the most feasible physical stressor as it allows scanning without losing image quality due to movement artefacts [
19].
Therefore, in a population-based prospective cohort study from early pregnancy onwards, we performed a cardiovascular stress test induced by isometric handgrip exercise combined with detailed measurements of the cardiovascular system. The objectives of this study were to develop a Cardiac Magnetic Resonance imaging (CMR) exercise study protocol using an isometric handgrip exercise in children, to demonstrate the feasibility and reproducibility of this protocol in a population-based cohort and to evaluate the cardiovascular response to exercise in a low-risk pediatric population.
Discussion
We performed a cardiovascular exercise test with detailed cardiovascular measurements in a pediatric population-based cohort study. We showed that a sustained handgrip exercise of 7 min at 30–40% MVC is a feasible exercise method in a healthy pediatric population to induce a cardiovascular exercise response. This handgrip exercise leads to significant increases in heart rate, blood pressure and cardiac left ventricular volumes.
Stress inducement by physical exercise requires major cardiovascular adaptations to maintain an adequate perfusion of the body. Cardiovascular exercise tests are widely used in clinical practice to reveal subtle cardiovascular pathology [
3,
32‐
34]. In addition to common measurements, CMR during exercise tests improves the value of the cardiovascular exercise tests as it allows detailed assessment of the structural and functional cardiac response to exercise without geometric assumptions of the ventricles [
33,
35,
36]. There are multiple methods available to induce the cardiovascular response to exercise. However, combined with CMR, cycling cannot be combined with long breath holds and a treadmill exercise is not feasible within the MRI. Isometric handgrip exercise is the most feasible physical stressor in combination with CMR as it allows scanning without losing image quality due to movement artefacts [
19]. This is the first large pediatric population-based cohort study exploring the cardiovascular effects of an isometric handgrip exercise combined with detailed cardiovascular measurements [
19].
The effects of isometric handgrip exercise on only simple measurements of the cardiovascular exercise response have been assessed by several small studies in children. In a population based study among 32 healthy children with a mean age of 15 years examining the cardiovascular exercise response to submaximal isometric handgrip, a sustained isometric handgrip exercise of 4 min at 25% MVC was performed, which led to an increase in heart rate of 25.7%, in systolic blood pressure of 12.7% and diastolic blood pressure of 24.6% [
37]. In other small clinical pediatric studies among children aged 10 to 18 years ranging from n = 19 to n = 47, heart rate increased up to 18 bpm, systolic blood pressure increased by 15 mmHg and diastolic blood pressure by 16 mmHg, induced by an isometric handgrip exercise at varying intensities and durations from 30 s to 4 min [
38‐
43]. As compared to these studies, our exercise protocol led to stronger effects on increases in heart rate, but lower effects on increases in blood pressure.
We observed a steep decline in heart rate and blood pressure after cessation of the exercise, and after 5 min cessation heartrate was lower and blood pressure was still higher than before exercising. In line with our findings, a study in 27 children aged 12 years measured the cardiovascular recovery reaction after a 3-min isometric handgrip exercise at 30%MVC and showed that the mean arterial pressure was slightly higher and heart rate was lower after a 3-min recovery than before exercising [
38]. Differences between our study and previous studies may be explained by differences in exercise protocol and cardiovascular assessment. Compared to previous studies, our exercise protocol was much longer to ensure that all CMR images were made while the cardiovascular system was at a stress state. Also, in our study, participants were in a supine position and had to hold their breath for cardiac imaging. Systemic vascular resistance at the start of supine exercise is lower and increases less than during erect exercise, therefor blood pressure changes are lower during supine exercise [
44,
45]. This may, at least partly, explain the differences between our results and those from previous studies. Thus, we showed that a sustained isometric handgrip exercise of 7 min at 30–40%MVC leads to a significant rise in heart rate and blood pressure, enabling the assessment of a cardiovascular exercise reaction by a simple, low-cost exercise.
In research settings, only few studies have investigated the cardiovascular stress response with exercise CMR in healthy populations and involved only adults. In the vast majority, an MRI compatible cycle or push–pull ergometer was used as exercise modality. A meta-analysis of 17 previous exercise CMR studies with a total of 226 healthy adult subjects, showed an increase in both heart rate and stroke volume in reaction to various forms of dynamic exercises (e.g. cycle, treadmill or custom made modality). The change in stroke volume was driven by a reduction in left ventricular end-systolic volume, with no change in left ventricular end-diastolic volume. Left ventricular ejection fraction slightly increased [
46]. There are only a few studies with relatively small sample sizes, examining the cardiovascular reaction on an isometric handgrip exercise measured by CMR. A study exploring the cardiovascular response to an isometric handgrip exercise of 6–8 min at 30% MVC in 53 healthy subjects with a mean age of 45 years found an increase in stroke volume from 78 to 80 ml/heartbeat [
35]. A study in 333 healthy subjects with a mean age of 53 years old explored the cardiovascular response to an isometric handgrip exercise of 3 min at 40% MVC measured by echocardiography. They found an increase in LVEDV, LVESV and stroke volume and a small decrease in ejection fraction [
47]. This study showed that younger subjects had a much higher increases in LVESV and LVEDV. A study in 75 healthy participants aged 38.8 ± 10.9 years, examined the effects of an isometric bicep exercise at 35% of maximum biceps force on ventricular outcomes measured by CMR. This study also showed an increase in LVEDV and LVESV (6.0% and 20.8%, respectively), decrease in LVEF (-6.3%) and unchanged stroke volume in response to exercise [
48]. In line with these studies in adult populations, we observed significant changes in LVEDV, LVESV, LVEF and cardiac output in response to isometric handgrip exercise. Stroke volume however remained unchanged. The small decrease in LVEF is in contrast with the effects of a dynamic exercise which increases LVEF [
49]. This can be explained by the increase in systemic vascular resistance during isometric exercise, whilst it decreases in response to dynamic exercise [
50]. As a result, isometric exercise causes a larger increase in afterload, which limits LV ejection through the force velocity relationship [
26]. Of all good quality CMR measurements during rest, we were able to use 184 CMR scans (89%) of good quality obtained during exercise. Due to time restriction, we scanned two slices per breath-hold resulting in longer breath-holds of maximal 15 s which were not feasible for some of the participants during the exercise, leading to breathing artefacts. Also, the ECG triggering of the scanner failed in some of the participants during the exercise causing low quality images which were not suitable for further analyses. We observed a good to excellent intra-observer reproducibility for the majority of volumetric and functional cardiac and aortic measurements obtained during rest and the cardiovascular exercise test [
51]. Only for LVEF, reproducibility was moderate. To improve reproducibility, we repeated a part of the training and applied stricter rules for identifying the left ventricular basal slice, including the rule that the basal slice may be defined by at least 50% of the blood volume surrounded by myocardium [
28]. Thus, our study shows that CMR during exercise is feasible in pediatric populations and leads to significant increases in LVEDV, LVESV and cardiac output with the strongest effect on LVEDV and LVESV. LVEF slightly decreased, in line with earlier research examining the effects of an isometric exercise.
We explored potential differences between girls and boys, as earlier studies describe different physical reactions to exercise according to sex [
52]. In girls, systolic blood pressure increased more during exercise and decreased faster after cessation of the exercise compared to boys. This is in contrast with earlier pediatric and adult studies finding stronger effects of exercise on heart rate and blood pressure in men [
47,
53] These differences may be due to the age of assesment and our exercise protocol. Further studies are needed to examine the differences in cardiovascular exercise reaction and explore the potential underlying mechanisms explaining differences in exercise response between boys and girls.
Future research
The findings from our study offer great opportunities for future research examining the effects of early life exposures on childhood cardiovascular development as a sustained isometric handgrip exercise can reveal subtle functional adaptations of the cardiovascular system that may not be present at rest. These results could aid in finding better screening modalities to identify children that are at an increased risk of future cardiovascular diseases and mortality. These findings are also important from a clinical perspective as these findings provide insight into the potential to perform an isometric handgrip exercise during cardiac MR scanning to induce a cardiovascular exercise response when pharmacological stressors are contraindicated or undesirable. However, 11% of our CMR scans during exercise were not of sufficient quality for assessment and were excluded from our analysis. Newer CMR techniques allow for real-time free breathing scanning during exercise with preservation of the image quality [
54]. A recent study even successfully developed a free-breathing and ECG free real-time cine for exercise CMR [
55]. This offers great opportunities for future CMR exercise studies.
In the current study we measured PWV during rest. Future studies should include measurements of PWV during rest and exercise to obtain a more complete overview of the cardiovascular exercise response. These PWV measurement should include additional calculation methods, like the location specific flow-area method (PWV
QA). This method correlates very well to the method used in the current study and allows for the calculation of regional differences in stiffness between the ascending and descending aorta [
57]. Additionally by using phase contrast MRI-derived flow and area waveforms, wave intensity analysis can be performed to obtain a non-invasive measurement of the arterial wall stiffness without the use of breath holds [
58]. More information on cardiac functioning during exercise could also be obtained by adding strain measurements to the analysis. This method differentiates between active and passive movement of myocardial segments and detects early subclinical signs of myocardial dysfunction [
56,
59].
In this study we found a small decrease in LVEF, which is contrary to the effects of dynamic exercise. Future studies should compare an isometric handgrip exercise with dynamic exercise to explore which method is more effective in discovering small subclinical differences in cardiovascular exercise reaction.
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