Heritability of the affective response to exercise and its correlation to exercise behavior.

OBJECTIVES: Individual differences in adolescent exercise behavior are strongly influenced by genetic factors. The affective response to exercise is a potential source of these genetic influences. To test its role in the motivation to exercise, we estimated the heritability of the affective responses during and after exercise and the overlap with the genetic factors influencing regular voluntary exercise behavior. DESIGN: 226 twin pairs and 38 siblings completed two submaximal exercise tests on a cycle ergometer and a treadmill and a maximal exercise test on a cycle ergometer. Affective responses were assessed by the Feeling Scale (FS), Borg's Rating of Perceived Exertion (RPE) and the Activation-Deactivation Adjective Checklist (AD ACL). METHODS: Multivariate structural equation modeling was used to estimate heritability of the affective responses during and after submaximal and maximal exercise and the (genetic) correlation with self-reported regular voluntary exercise behavior over the past year. RESULTS: Genetic factors explained 15% of the individual differences in FS responses during the cycle ergometer test, as well as 29% and 35% of the individual differences in RPE during the cycle ergometer and treadmill tests, respectively. For the AD ACL scales, heritability estimates ranged from 17% to 37% after submaximal exercise and from 12% to 37% after maximal exercise. Without exception, more positive affective responses were associated with higher amounts of regular exercise activity (.15 < r < .21) and this association was accounted for by an overlap in genetic factors influencing affective responding and exercise behavior. CONCLUSIONS: We demonstrate low to moderate heritability estimates for the affective response during and after exercise and significant (genetic) associations with regular voluntary exercise behavior. These innate individual differences in the affective responses to exercise should be taken into account in interventions aiming to motivate adolescents to adopt and maintain regular exercise.

Twin-sibling study and meta-analysis on the heritability of maximal oxygen consumption.

Large individual differences exist in aerobic fitness in childhood and adolescence, but the relative contribution of genetic factors to this variation remains to be established. In a sample of adolescent twins and siblings (n = 479), heart rate (HR) and maximal oxygen uptake (V̇o2max) were recorded during the climax of a graded maximal exercise test. In addition, V̇o2max was predicted in two graded submaximal exercise tests on the cycle ergometer and the treadmill, using extrapolation of the HR/V̇o2 curve to the predicted HRmax. Heritability estimates for measured V̇o2max were 60% in ml/min and 55% for V̇o2max in ml·min(-1)·kg(-1). Phenotypic correlations between measured V̇o2max and predicted V̇o2max from either submaximal treadmill or cycle ergometer tests were modest (0.57 < r < 0.70), in part because of the poor agreement between predicted and actual HRmax. The majority of this correlation was explained by genetic factors; therefore, the submaximal exercise tests still led to very comparable estimates of heritability of V̇o2max. To arrive at a robust estimate for the heritability of V̇o2max in children to young adults, a sample size weighted meta-analysis was performed on all extant twin and sibling studies in this age range. Eight studies, including the current study, were meta-analyzed and resulted in a weighted heritability estimate of 59% (ml/min) and 72% (ml·min(-1)·kg(-1)) for V̇o2max. Taken together, the twin-sibling study and meta-analyses showed that from childhood to early adulthood genetic factors determine more than half of the individual differences in V̇o2max.

Differences in Adolescent Physical Fitness: A Multivariate Approach and Meta-analysis.

Physical fitness can be defined as a set of components that determine exercise ability and influence performance in sports. This study investigates the genetic and environmental influences on individual differences in explosive leg strength (vertical jump), handgrip strength, balance, and flexibility (sit-and-reach) in 227 healthy monozygotic and dizygotic twin pairs and 38 of their singleton siblings (mean age 17.2 ± 1.2). Heritability estimates were 49% (95% CI 35-60%) for vertical jump, 59% (95% CI 46-69%) for handgrip strength, 38% (95% CI 22-52%) for balance, and 77% (95% CI 69-83%) for flexibility. In addition, a meta-analysis was performed on all twin studies in children, adolescents and young adults reporting heritability estimates for these phenotypes. Fifteen studies, including results from our own study, were meta-analyzed by computing the weighted average heritability. This showed that genetic factors explained most of the variance in vertical jump (62%; 95% CI 47-77%, N = 874), handgrip strength (63%; 95% CI 47-73%, N = 4516) and flexibility (50%; 95% CI 38-61%, N = 1130) in children and young adults. For balance this was 35% (95% CI 19-51%, N = 978). Finally, multivariate modeling showed that the phenotypic correlations between the phenotypes in current study (0.07 < r < 0.27) were mostly driven by genetic factors. It is concluded that genetic factors contribute significantly to the variance in muscle strength, flexibility and balance; factors that may play a key role in the individual differences in adolescent exercise ability and sports performance.

Heritability of heart rate recovery and vagal rebound after exercise.

PURPOSE: The prognostic power of heart rate recovery (HRR) after exercise has been well established but the exact origin of individual differences in HRR remains unclear. This study aims to estimate the heritability of HRR and vagal rebound after maximal exercise in adolescents. Furthermore, the role of voluntary regular exercise behavior (EB) in HRR and vagal rebound is tested. METHODS: 491 healthy adolescent twins and their siblings were recruited for maximal exercise testing, followed by a standardized cooldown with measurement of the electrocardiogram and respiratory frequency. Immediate and long-term HRR (HRR60 and HRR180) and vagal rebound (heart rate variability in the respiratory frequency range) were assessed 1 and 3 min after exercise. Multivariate twin modeling was used to estimate heritability of all measured variables and to compute the genetic contribution to their covariance. RESULTS: Heritability of HRR60, HRR180 and immediate and long-term vagal rebound is 60 % (95 % CI: 48-67), 65 % (95 % CI: 54-73), 23 % (95 % CI: 11-35) and 3 % (95 % CI: 0-11), respectively. We find evidence for two separate genetic factors with one factor influencing overall cardiac vagal control, including resting heart rate and respiratory sinus arrhythmia, and a specific factor for cardiac vagal exercise recovery. EB was only modestly associated with resting heart rate (r = -0.27) and HRR (rHRR60 = 0.10; rHRR180 = 0.19) with very high genetic contribution to these associations (88-91 %). CONCLUSIONS: Individual differences in HRR and immediate vagal rebound can to a large extent be explained by genetic factors. These innate cardiac vagal exercise recovery factors partly reflect the effects of heritable differences in EB.

Accelerated sinus rhythm prevents catecholaminergic polymorphic ventricular tachycardia in mice and in patients.

RATIONALE: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in cardiac ryanodine receptor (RyR2) or calsequestrin (Casq2) genes. Sinoatrial node dysfunction associated with CPVT may increase the risk for ventricular arrhythmia (VA). OBJECTIVE: To test the hypothesis that CPVT is suppressed by supraventricular overdrive stimulation. METHODS AND RESULTS: Using CPVT mouse models (Casq2(-/-) and RyR2(R4496C/+) mice), the effect of increasing sinus heart rate was tested by pretreatment with atropine and by atrial overdrive pacing. Increasing intrinsic sinus rate with atropine before catecholamine challenge suppressed ventricular tachycardia in 86% of Casq2(-/-) mice (6/7) and significantly reduced the VA score (atropine: 0.6±0.2 versus vehicle: 1.7±0.3; P<0.05). Atrial overdrive pacing completely prevented VA in 16 of 19 (84%) Casq2(-/-) and in 7 of 8 (88%) RyR2(R4496C/+) mice and significantly reduced ventricular premature beats in both CPVT models (P<0.05). Rapid pacing also prevented spontaneous calcium waves and triggered beats in isolated CPVT myocytes. In humans, heart rate dependence of CPVT was evaluated by screening a CPVT patient registry for antiarrhythmic drug-naïve individuals that reached >85% of their maximum-predicted heart rate during exercise testing. All 18 CPVT patients who fulfilled the inclusion criteria exhibited VA before reaching 87% of maximum heart rate. In 6 CPVT patients (33%), VA were paradoxically suppressed as sinus heart rates increased further with continued exercise. CONCLUSIONS: Accelerated supraventricular rates suppress VAs in 2 CPVT mouse models and in a subset of CPVT patients. Hypothetically, atrial overdrive pacing may be a therapy for preventing exercise-induced ventricular tachycardia in treatment-refractory CPVT patients.

Comparing the diagnostic considerations between general practitioners with a special interest in cardiovascular disease and those without in patients with symptoms suggestive of heart failure: a vignette study.

BACKGROUND: General practitioners (GPs) specialized in cardiovascular disease (GPSI-CVD) may suspect heart failure (HF) more easily than GPs not specialized in CVD. We assessed whether GPSI-CVD consider investigations aimed at detecting HF more often than other GPs in two clinical scenarios of an older male person with respiratory and suggestive HF symptoms. METHODS: In this vignette study, Dutch GPs evaluated two vignettes. The first involved a 72-year-old man with hypertension and a 30 pack-year smoking history who presented himself with symptoms of a common cold, but also shortness of breath, reduced exercise tolerance, and signs of fluid overload. The second vignette was similar but now the 72-year-old man was known with chronic obstructive pulmonary disease (COPD). GPs could select diagnostic tests from a multiple-choice list with answer options targeted at HF, COPD or exacerbation of COPD, or lower respiratory tract infection. With Pearson Chi-square or Fisher's exact test differences between the two GP groups were assessed regarding the chosen diagnostic tests. RESULTS: Of the 148 participating GPs, 25 were GPSI-CVD and 123 were other GPs. In the first vignette, GPSI-CVD more often considered performing electrocardiography (ECG) than other GPs (64.0% vs. 32.5%, p = 0.003). In the second vignette, GPSI-CVD were more inclined to perform both ECG (36.0% vs. 12.2%, p = 0.003) and natriuretic peptide testing (56.0% vs. 32.5%, p = 0.006). CONCLUSIONS: Most GPs seemed to consider multiple diagnoses, including HF, with GPSI-CVD more likely performing ECG and natriuretic peptide testing in an older male person with both respiratory and suggestive HF symptoms.

Maturation of the Cardiac Autonomic Nervous System Activity in Children and Adolescents.

Background Despite the increasing interest in cardiac autonomic nervous activity, the normal development is not fully understood. The main aim was to determine the maturation of different cardiac sympathetic-(SNS) and parasympathetic nervous system (PNS) activity parameters in healthy patients aged 0.5 to 20 years. A second aim was to determine potential sex differences. Methods and Results Five studies covering the 0.5- to 20-year age range provided impedance- and electrocardiography recordings from which heart rate, different PNS-parameters (eg, respiratory sinus arrhythmia) and an SNS-parameter (pre-ejection period) were collected. Age trends were computed in the mean values across 12 age-bins and in the age-specific variances. Age was associated with changes in mean and variance of all parameters. PNS-activity followed a cubic trend, with an exponential increase from infancy, a plateau phase during middle childhood, followed by a decrease to adolescence. SNS-activity showed a more linear trend, with a gradual decrease from infancy to adolescence. Boys had higher SNS-activity at ages 11 to 15 years, while PNS-activity was higher at 5 and 11 to 12 years with the plateau level reached earlier in girls. Interindividual variation was high at all ages. Variance was reasonably stable for SNS- and the log-transformed PNS-parameters. Conclusions Cardiac PNS- and SNS-activity in childhood follows different maturational trajectories. Whereas PNS-activity shows a cubic trend with a plateau phase during middle childhood, SNS-activity shows a linear decrease from 0.5 to 20 years. Despite the large samples used, clinical use of the sex-specific centile and percentile normative values is modest in view of the large individual differences, even within narrow age bands.

The effects of age at correction of aortic coarctation and recurrent obstruction on adolescent patients: MRI evaluation of wall shear stress and pulse wave velocity.

BACKGROUND: Coarctation patients before curative reconstruction are exposed to abnormal flow patterns which potentially could cause wall deterioration. This study evaluated the effect of age at correction on the pulse wave velocity (PWV) and peak wall shear stress (WSS) in adolescent patients with corrected coarctation. Effects of valve morphology and presence of reobstruction were also evaluated. METHODS: Twenty-one patients aged 13.7 ± 2.6 years (mean ± standard deviation) were included (bicuspid aortic valve, n = 14; reobstruction, n = 9). Mean age at correction was 1.0 ± 1.8 years. PWV was determined from two high-temporal through-plane phase-contrast magnetic resonance imaging (MRI) acquisitions, for two segments: ascending aorta plus aortic arch and descending aorta. WSS was determined from four-dimensional flow MRI. Peak WSS over five systolic phases was determined for ascending aorta, aortic arch, and descending aorta. RESULTS: Patients with tricuspid aortic valve showed a significant correlation between the age at correction and descending aorta PWV (rs = 0.80, p = 0.010). Significant differences were found between patients without and with reobstruction for peak WSS in the aortic arch (3.9 ± 1.3 Pa versus 6.5 ± 2.2 Pa, respectively; p = 0.003) and descending aorta (5.0 ± 1.3 Pa versus 6.7 ± 1.1 Pa, respectively; p = 0.005). CONCLUSIONS: A prolonged period of abnormal haemodynamic exposure may result in increased aortic wall stiffening. The increased peak WSS as results of a reobstruction possibly promotes different disease progression, which endorse longitudinal follow-up examination of corrected coarctation patients.

Long-term follow-up after ventricular septal defect repair in children: cardiac autonomic control, cardiac function and exercise capacity.

OBJECTIVES: Survival after surgical repair of a ventricular septal defect (VSD) is good, but, as in almost all congenital heart diseases, late complications are frequent in adulthood. The exact mechanisms, timing and who is at risk are not fully understood. Altered cardiac autonomic nervous system (ANS) activity might play a role in these long-term sequelae. The aim of this study was to extensively evaluate children late after VSD repair including their cardiac ANS activity, cardiac function and exercise capacity. METHODS: Thirty-three patients after surgical VSD repair and 66 healthy age-matched controls underwent 24-h monitoring of ANS control and cardiac output using impedance cardiography, detailed echocardiography and cardiopulmonary exercise testing. RESULTS: Ambulatory cardiac ANS control was not different between the patients and the controls. Right ventricular function, exercise capacity and ambulatory cardiac output were decreased in patients compared with the controls. No relationships were found between cardiac ANS activity and cardiac function. CONCLUSIONS: Long (average time after repair was 9.9 years) after successful surgical correction of a VSD, cardiac ANS control is not different from the controls. Right ventricular function and exercise capacity are impaired in VSD patients. Post-surgical outcome in these patients may be less benign than presently assumed; therefore, follow-up should be continued into adulthood to detect adverse outcomes in a timely fashion.

Cardiac Autonomic Nervous System Activity and Cardiac Function in Children After Coarctation Repair.

BACKGROUND: Coarctation of the aorta (CoA) is one of the most common congenital heart defects. Most patients live into adulthood as a result of improved surgical techniques; however, late complications, including hypertension, recoarctation, and arrhythmias, are common. The autonomic nervous system (ANS) might play a role in the pathology. This study evaluated cardiac ANS activity and cardiac function in children after CoA repair and investigated the relationship between the two. METHODS: The study participants were 31 children after CoA repair and 62 healthy controls aged between 8 and 18 years. Ambulatory impedance cardiography was used to measure cardiac ANS activity and cardiac output for 24 hours. Transthoracic echocardiography and cardiac magnetic resonance imaging were used to measure cardiac function. RESULTS: No group differences were found in ambulatory cardiac ANS activity. However, ambulatory cardiac output and left ventricular function were significantly decreased in patients compared with controls. CONCLUSIONS: Left ventricular function and ambulatory cardiac output are impaired in patients after CoA repair, despite unchanged cardiac ANS activity in this group. These results underscore the importance of clinical follow-up, even in patients without residual stenosis.

Impedance cardiography in healthy children and children with congenital heart disease: Improving stroke volume assessment.

INTRODUCTION: Stroke volume (SV) and cardiac output are important measures in the clinical evaluation of cardiac patients and are also frequently used in research applications. This study was aimed to improve SV scoring derived from spot-electrode based impedance cardiography (ICG) in a pediatric population of healthy volunteers and patients with a corrected congenital heart defect. METHODS: 128 healthy volunteers and 66 patients participated. First, scoring methods for ambiguous ICG signals were optimized to improve agreement of B- and X-points with aortic valve opening/closure in simultaneously recorded transthoracic echocardiography (TTE). Building on the improved scoring of B- and X-points, the Kubicek equation for SV estimation was optimized by testing the agreement with the simultaneously recorded SV by TTE. Both steps were initially done in a subset of the sample of healthy children and then validated in the remaining subset of healthy children and in a sample of patients. RESULTS: SV assessment by ICG in healthy children strongly improved (intra class correlation increased from 0.26 to 0.72) after replacing baseline thorax impedance (Z0) in the Kubicek equation by an equation (7.337-6.208∗dZ/dtmax), where dZ/dtmax is the amplitude of the ICG signal at the C-point. Reliable SV assessment remained more difficult in patients compared to healthy controls. CONCLUSIONS: After proper adjustment of the Kubicek equation, SV assessed by the use of spot-electrode based ICG is comparable to that obtained from TTE. This approach is highly feasible in a pediatric population and can be used in an ambulatory setting.

Postnatal Cardiac Autonomic Nervous Control in Pediatric Congenital Heart Disease.

Congenital heart disease is the most common congenital defect. During childhood, survival is generally good but, in adulthood, late complications are not uncommon. Abnormal autonomic control in children with congenital heart disease may contribute considerably to the pathophysiology of these long term sequelae. This narrative review of 34 studies aims to summarize current knowledge on function of the autonomic nervous system in children with a congenital heart defect. Large scale studies that measure both branches of the nervous system for prolonged periods of time in well-defined patient cohorts in various phases of childhood and adolescence are currently lacking. Pending such studies, there is not yet a good grasp on the extent and direction of sympathetic and parasympathetic autonomic function in pediatric congenital heart disease. Longitudinal studies in homogenous patient groups linking autonomic nervous system function and clinical outcome are warranted.

Familial evaluation in catecholaminergic polymorphic ventricular tachycardia: disease penetrance and expression in cardiac ryanodine receptor mutation-carrying relatives.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome associated with mutations in the cardiac ryanodine receptor gene (Ryr2) in the majority of patients. Previous studies of CPVT patients mainly involved probands, so current insight into disease penetrance, expression, genotype-phenotype correlations, and arrhythmic event rates in relatives carrying the Ryr2 mutation is limited. METHODS AND RESULTS: One-hundred sixteen relatives carrying the Ryr2 mutation from 15 families who were identified by cascade screening of the Ryr2 mutation causing CPVT in the proband were clinically characterized, including 61 relatives from 1 family. Fifty-four of 108 antiarrhythmic drug-free relatives (50%) had a CPVT phenotype at the first cardiological examination, including 27 (25%) with nonsustained ventricular tachycardia. Relatives carrying a Ryr2 mutation in the C-terminal channel-forming domain showed an increased odds of nonsustained ventricular tachycardia (odds ratio, 4.1; 95% CI, 1.5-11.5; P=0.007, compared with N-terminal domain) compared with N-terminal domain. Sinus bradycardia was observed in 19% of relatives, whereas other supraventricular dysrhythmias were present in 16%. Ninety-eight (most actively treated) relatives (84%) were followed up for a median of 4.7 years (range, 0.3-19.0 years). During follow-up, 2 asymptomatic relatives experienced exercise-induced syncope. One relative was not being treated, whereas the other was noncompliant. None of the 116 relatives died of CPVT during a 6.7-year follow-up (range, 1.4-20.9 years). CONCLUSIONS: Relatives carrying an Ryr2 mutation show a marked phenotypic diversity. The vast majority do not have signs of supraventricular disease manifestations. Mutation location may be associated with severity of the phenotype. The arrhythmic event rate during follow-up was low.