The efficacy of the use of atropine in children with reflex anoxic syncope during pallid breath-holding spells: can cardiac pacemaker implantation be avoided?

OBJECTIVES: Reflex anoxic syncope is the result of an overreaction of the vagal system, resulting in hypotension and bradycardia or brief cardiac arrest. Because of the benign character and the absence of complications in short or long term, treatment is only necessary in case of frequent or severe clinical presentation. Treatment options are anticholinergic drugs or cardiac pacemaker placement. We investigated atropine treatment and aimed to examine if pacemaker placement can be avoided. METHODS: We retrospectively reviewed patients treated with atropine for severe reflex anoxic syncope in our centre from January 2017 until May 2023, and compared our results to those in the literature. RESULTS: The study population consisted of 10 children, 70% female, with an age ranging from 5 months to 3 years (mean 14.5 months) when atropine treatment was started (dose 17-50 microg/kg/day). All patient's parents reported adequate symptom management during atropine treatment, with complete resolution in 10%. Minor side effects were reported in 60% (dry mucosa in 40%, obstipation in 20%, and nausea or blurry vision in 10%). DISCUSSION: We consider atropine a safe and effective treatment to manage reflex anoxic syncope with similar success rate to pacemaker implantation. However, pacemaker implantation entails substantial risk for complications (up to 25%) such as infection or technical problems and morbidity such as scar formation. This might be considered redundant for a benign and temporary condition, certainly given the possibility of other efficient treatment options. Consequently, we recommend atropine treatment over implantation of a cardiac pacemaker in children with severe reflex anoxic syncope.

Exploring the Mutational Landscape of Isolated Congenital Heart Defects: An Exome Sequencing Study Using Cardiac DNA.

Congenital heart defects (CHD) are the most common congenital anomalies in liveborn children. In contrast to syndromic CHD (SCHD), the genetic basis of isolated CHD (ICHD) is complex, and the underlying pathogenic mechanisms appear intricate and are incompletely understood. Next to rare Mendelian conditions, somatic mosaicism or a complex multifactorial genetic architecture are assumed for most ICHD. We performed exome sequencing (ES) in 73 parent-offspring ICHD trios using proband DNA extracted from cardiac tissue. We identified six germline de novo variants and 625 germline rare inherited variants with 'damaging' in silico predictions in cardiac-relevant genes expressed in the developing human heart. There were no CHD-relevant somatic variants. Transmission disequilibrium testing (TDT) and association testing (AT) yielded no statistically significant results, except for the AT of missense variants in cilia genes. Somatic mutations are not a common cause of ICHD. Rare de novo and inherited protein-damaging variants may contribute to ICHD, possibly as part of an oligogenic or polygenic disease model. TDT and AT failed to provide informative results, likely due to the lack of power, but provided a framework for future studies in larger cohorts. Overall, the diagnostic value of ES on cardiac tissue is limited in individual ICHD cases.

Clinical Features and Natural History of Preadolescent Nonsyndromic Hypertrophic Cardiomyopathy.

BACKGROUND: Up to one-half of childhood sarcomeric hypertrophic cardiomyopathy (HCM) presents before the age of 12 years, but this patient group has not been systematically characterized. OBJECTIVES: The aim of this study was to describe the clinical presentation and natural history of patients presenting with nonsyndromic HCM before the age of 12 years. METHODS: Data from the International Paediatric Hypertrophic Cardiomyopathy Consortium on 639 children diagnosed with HCM younger than 12 years were collected and compared with those from 568 children diagnosed between 12 and 16 years. RESULTS: At baseline, 339 patients (53.6%) had family histories of HCM, 132 (20.9%) had heart failure symptoms, and 250 (39.2%) were prescribed cardiac medications. The median maximal left ventricular wall thickness z-score was 8.7 (IQR: 5.3-14.4), and 145 patients (27.2%) had left ventricular outflow tract obstruction. Over a median follow-up period of 5.6 years (IQR: 2.3-10.0 years), 42 patients (6.6%) died, 21 (3.3%) underwent cardiac transplantation, and 69 (10.8%) had life-threatening arrhythmic events. Compared with those presenting after 12 years, a higher proportion of younger patients underwent myectomy (10.5% vs 7.2%; P = 0.045), but fewer received primary prevention implantable cardioverter-defibrillators (18.9% vs 30.1%; P = 0.041). The incidence of mortality or life-threatening arrhythmic events did not differ, but events occurred at a younger age. CONCLUSIONS: Early-onset childhood HCM is associated with a comparable symptom burden and cardiac phenotype as in patients presenting later in childhood. Long-term outcomes including mortality did not differ by age of presentation, but patients presenting at younger than 12 years experienced adverse events at younger ages.

Relationship Between Maximal Left Ventricular Wall Thickness and Sudden Cardiac Death in Childhood Onset Hypertrophic Cardiomyopathy.

BACKGROUND: Maximal left ventricular wall thickness (MLVWT) is a risk factor for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). In adults, the severity of left ventricular hypertrophy has a nonlinear relationship with SCD, but it is not known whether the same complex relationship is seen in childhood. The aim of this study was to describe the relationship between left ventricular hypertrophy and SCD risk in a large international pediatric HCM cohort. METHODS: The study cohort comprised 1075 children (mean age, 10.2 years [±4.4]) diagnosed with HCM (1-16 years) from the International Paediatric Hypertrophic Cardiomyopathy Consortium. Anonymized, noninvasive clinical data were collected from baseline evaluation and follow-up, and 5-year estimated SCD risk was calculated (HCM Risk-Kids). RESULTS: MLVWT Z score was <10 in 598 (58.1%), ≥10 to <20 in 334 (31.1%), and ≥20 in 143 (13.3%). Higher MLVWT Z scores were associated with heart failure symptoms, unexplained syncope, left ventricular outflow tract obstruction, left atrial dilatation, and nonsustained ventricular tachycardia. One hundred twenty-two patients (71.3%) with MLVWT Z score ≥20 had coexisting risk factors for SCD. Over a median follow-up of 4.9 years (interquartile range, 2.3-9.3), 115 (10.7%) had an SCD event. Freedom from SCD event at 5 years for those with MLVWT Z scores <10, ≥10 to <20, and ≥20 was 95.6%, 87.4%, and 86.0, respectively. The estimated SCD risk at 5 years had a nonlinear, inverted U-shaped relationship with MLVWT Z score, peaking at Z score +23. The presence of coexisting risk factors had a summative effect on risk. CONCLUSIONS: In children with HCM, an inverted U-shaped relationship exists between left ventricular hypertrophy and estimated SCD risk. The presence of additional risk factors has a summative effect on risk. While MLVWT is important for risk stratification, it should not be used either as a binary variable or in isolation to guide implantable cardioverter defibrillator implantation decisions in children with HCM.

A Reassessment of Copy Number Variations in Congenital Heart Defects: Picturing the Whole Genome.

Copy number variations (CNVs) can modulate phenotypes by affecting protein-coding sequences directly or through interference of gene expression. Recent studies in cancer and limb defects pinpointed the relevance of non-coding gene regulatory elements such as long non-coding RNAs (lncRNAs) and topologically associated domain (TAD)-related gene-enhancer interactions. The contribution of such non-coding elements is largely unexplored in congenital heart defects (CHD). We performed a retrospective analysis of CNVs reported in a cohort of 270 CHD patients. We reviewed the diagnostic yield of pathogenic CNVs, and performed a comprehensive reassessment of 138 CNVs of unknown significance (CNV-US), evaluating protein-coding genes, lncRNA genes, and potential interferences with TAD-related gene-enhancer interactions. Fifty-two of the 138 CNV-US may relate to CHD, revealing three candidate CHD regions, 19 candidate CHD genes, 80 lncRNA genes of interest, and six potentially CHD-related TAD interferences. Our study thus indicates a potential relevance of non-coding gene regulatory elements in CNV-related CHD pathogenesis. Shortcomings in our current knowledge on genomic variation call for continuous reporting of CNV-US in international databases, careful patient counseling, and additional functional studies to confirm these preliminary findings.

Paediatric subaortic stenosis: long-term outcome and risk factors for reoperation.

OBJECTIVES: Surgical repair of subaortic stenosis (SAS) is associated with a substantial reoperation risk. We aimed to identify risk factors for reintervention in relation to discrete and tunnel-type SAS morphology. METHODS: Single-centre retrospective study of paediatric SAS diagnosed between 1992 and 2017. Multivariable Cox regression analysis was performed to identify reintervention risk factors. RESULTS: Eighty-five children [median age 2.5 (0.7-6.5) years at diagnosis] with a median follow-up of 10.1 (5.5-16.4) years were included. Surgery was executed in 83% (n = 71). Freedom from reoperation was 88 ± 5% at 5 years and 82 ± 6% at 10 years for discrete SAS, compared to, respectively, 33 ± 16% and 17 ± 14% for tunnel-type SAS (log-rank P < 0.001). Independent risk factors for reintervention were a postoperative gradient >20 mmHg [hazard ratio (HR) 6.56, 95% confidence interval (CI) 1.41-24.1; P = 0.005], tunnel-type SAS (HR 7.46, 95% CI 2.48-22.49; P < 0.001), aortic annulus z-score <-2 (HR 11.07, 95% CI 3.03-40.47; P < 0.001) and age at intervention <2 years (HR 3.24, 95% CI 1.09-9.86; P = 0.035). Addition of septal myectomy at initial intervention was not associated with lesser reintervention. Fourteen children with a lower left ventricular outflow tract (LVOT) gradient (P < 0.001) and older age at diagnosis (P = 0.024) were followed expectatively. CONCLUSIONS: Children with SAS remain at risk for reintervention, despite initially effective LVOT relief. Regardless of SAS morphology, age <2 years at first intervention, a postoperative gradient >20 mmHg and presence of a hypoplastic aortic annulus are independent risk factors for reintervention. More extensive LVOT surgery might be considered at an earlier stage in these children. SAS presenting in older children with a low LVOT gradient at diagnosis shows little progression, justifying an expectative approach.

QRS Duration During Follow-Up of Tetralogy of Fallot: How Valuable is it? Analysis of ECG Changes in Relation to Pulmonary Valve Implantation.

Long-term results after tetralogy of Fallot (TOF) repair are determined by the extent of right ventricular remodeling to chronic pulmonary regurgitation entailing progressive RV dysfunction and a risk of developing ventricular arrhythmia. Pulmonary valve replacement (PVR) can alleviate this burden. As a predictor of ventricular arrhythmia, QRS duration remains a strong parameter in this decision. We performed a retrospective analysis of all PVR patients between 2005 and 2018, studying the time evolution of electrocardiographic parameters before and after PVR through linear mixed model analysis. 42 TOF patients underwent PVR. The median timespan between primary repair and PVR was 18 years (IQR 13-30). The indication for PVR was primarily based on the association of exercise intolerance (67%) and significant RV dilation on cMRI (median RVEDVi 161 ml/m2 IQR 133-181). Median QRS length was 155 ms (IQR 138-164), 4 (10%) patients had a QRS > 180 ms. QRS duration increased significantly before PVR, but barely showed regression after PVR. Changes of QRS duration after PVR were independent of RV dilation. In conclusion, when the decision for PVR in TOF patients is primarily based on RV volume and/or function threshold, QRS duration > 180 ms is rarely observed. In contrast with the significant increase of QRS duration before PVR, QRS length regression appears to be independent of the extent of RV dilation or QRS > 160 ms. Considering that the decision for PVR is based on mechanical RV characteristics, the utility of serial follow-up of QRS duration in contemporary operated TOF patients becomes questionable in absence of clinical arguments for ventricular arrhythmia.

Analysis of the recovery phase after maximal exercise in children with repaired tetralogy of Fallot and the relationship with ventricular function.

BACKGROUND: Few studies demonstrate delayed recovery after exercise in children and adults with heart disease. We assess the recovery patterns of gas exchange parameters and heart rate (HR) in children with repaired Tetralogy of Fallot (rToF) compared to healthy peers and investigate the correlation with ventricular function and QRS duration. METHODS: 45 children after rToF and 45 controls performed a maximal incremental cardiopulmonary exercise test. In the subsequent recovery period, patterns of VO2, VCO2 and HR were analysed. Half-life time (T1/2) of the exponential decay and drop per minute (Recmin) were compared between groups. In the rToF group, correlations were examined between the recovery parameters and QRS-duration and ventricular function, described by fractional shortening (FS) and tricuspid annular plane systolic excursion (TAPSE) measured at baseline prior to exercise. RESULTS: Recovery of VO2 and VCO2 was delayed in rToF patients, half-life time values were higher compared to controls (T1/2VO2 52.51 ±11.29 s vs. 44.31 ± 10.47 s; p = 0.001 and T1/2VCO2 68.28 ± 13.84 s vs. 59.41 ± 12.06 s; p = 0.002) and percentage drop from maximal value was slower at each minute of recovery (p<0.05). Correlations were found with FS (T1/2VO2: r = -0.517; p<0.001; Rec1minVO2: r = -0.636, p<0.001; Rec1minVCO2: r = -0.373, p = 0.012) and TAPSE (T1/2VO2: r = -0.505; p<0.001; Rec1minVO2: r = -0.566, p<0.001; T1/2VCO2: r = -0.466; p = 0.001; Rec1minVCO2: r = -0.507, p<0.001), not with QRS-duration. No difference was found in HR recovery between patients and controls. CONCLUSIONS: Children after rToF show a delayed gas exchange recovery after exercise. This delay correlates to ventricular function, demonstrating its importance in recovery after physical activity.

Myocardial disease and ventricular arrhythmia in Marfan syndrome: a prospective study.

BACKGROUND: Aortic root dilatation and-dissection and mitral valve prolapse are established cardiovascular manifestations in Marfan syndrome (MFS). Heart failure and arrhythmic sudden cardiac death have emerged as additional causes of morbidity and mortality. METHODS: To characterize myocardial dysfunction and arrhythmia in MFS we conducted a prospective longitudinal case-control study including 86 patients with MFS (55.8% women, mean age 36.3 yr-range 13-70 yr-) and 40 age-and sex-matched healthy controls. Cardiac ultrasound, resting and ambulatory ECG (AECG) and NT-proBNP measurements were performed in all subjects at baseline. Additionally, patients with MFS underwent 2 extra evaluations during 30 ± 7 months follow-up. To study primary versus secondary myocardial involvement, patients with MFS were divided in 2 groups: without previous surgery and normal/mild valvular function (MFS-1; N = 55) and with previous surgery or valvular dysfunction (MFS-2; N = 31). RESULTS: Compared to controls, patients in MFS-1 showed mild myocardial disease reflected in a larger left ventricular end-diastolic diameter (LVEDD), lower TAPSE and higher amount of (supra) ventricular extrasystoles [(S)VES]. Patients in MFS-2 were more severely affected. Seven patients (five in MFS-2) presented decreased LV ejection fraction. Twenty patients (twelve in MFS-2) had non-sustained ventricular tachycardia (NSVT) in at least one AECG. Larger LVEDD and higher amount of VES were independently associated with NSVT. CONCLUSION: Our study shows mild but significant myocardial involvement in patients with MFS. Patients with previous surgery or valvular dysfunction are more severely affected. Evaluation of myocardial function with echocardiography and AECG should be considered in all patients with MFS, especially in those with valvular disease and a history of cardiac surgery.

Compound Heterozygous SCN5A Mutations in Severe Sodium Channelopathy With Brugada Syndrome: A Case Report.

Aims: Brugada syndrome (BrS) is an inherited cardiac arrhythmia with an increased risk for sudden cardiac death (SCD). About 20% of BrS cases are explained by mutations in the SCN5A gene, encoding the main cardiac sodium Nav1.5 channel. Here we present a severe case of cardiac sodium channelopathy with BrS caused by SCN5A compound heterozygous mutations. We performed a genetic analysis of SCN5A in a male proband who collapsed during cycling at the age of 2 years. Because of atrial standstill, he received a pacemaker, and at the age of 3 years, he experienced a collapse anew with left-sided brain stroke. A later ECG taken during a fever unmasked a characteristic BrS type-1 pattern. The functional effect of the detected genetic variants was investigated. Methods and Results: Next-generation sequencing allowed the detection of two SCN5A variants in trans: c.4813+3_4813+6dupGGGT-a Belgian founder mutation-and c.4711 T>C, p.Phe1571Leu. A familial segregation analysis showed the presence of the founder mutation in the proband's affected father and paternal aunt and the de novo occurrence of the p.Phe1571Leu. The functional effect of the founder mutation was previously described as a loss-of-function. We performed a functional analysis of the p.Phe571Leu variant in HEK293 cells alone or co-expressed with the ß1-subunit. Compared to the SCN5A wild type, p.Phe1571Leu displayed a hyperpolarizing shift in the voltage dependence of inactivation (loss-of-function), while the activation parameters were unaffected. Using the peptide toxin nemertide α-1, the variant's loss-of-function effect could be restored due to a toxin-dependent reduction of channel inactivation. Conclusion: This is the first report providing support for the pathogenicity of the p.Phe1571Leu SCN5A variant which, together with the c.4813+3_4813+6dupGGGT founder mutation, explains the severity of the phenotype of cardiac sodium channelopathy with BrS in the presented case.

Study of the time-relationship of the mechano-electrical interaction in an animal model of tetralogy of Fallot: implications for the risk assessment of ventricular arrhythmias.

OBJECTIVES: The long-term outcome of tetralogy of Fallot (TOF) is determined by progressive right ventricular (RV) dysfunction through pulmonary regurgitation (PR) and the risk of malignant arrhythmia. Although mechano-electrical coupling in TOF is well-known, its time effect on the inducibility of arrhythmia remains ill-defined. The goal of this study was to investigate the mechano-electrical properties at different times in animals with chronic PR. METHODS: PR was induced by a transannular patch with limited RV scarring in infant pigs. Haemodynamic assessment included biventricular pressure-volume loops after 3 (n = 8) and 6 months (n = 7) compared to controls (n = 5). The electrophysiological study included endocardial monophasic action potential registration, intraventricular conduction velocity and induction of ventricular arrhythmia by burst pacing. RESULTS: Progressive RV dilation was achieved at 6 months (RV end-diastolic volume 143 ± 13 ml/m2-RV end-systolic volume 96 ± 7 ml/m2; P < 0.001), in association with depressed RV contractility (preload recruitable stroke work-slope: 19 ± 1 and 11 ± 3 Mw.ml-1.s-1 for control and 6 m; P < 0.001) and left ventricular contractility (preload recruitable stroke work-slope: 60 ± 13 and 40 ± 11 Mw.ml-1.s-1 for control and 6 m; P = 0.005). Concomitant to QRS prolongation, monophasic action potential90-duration and dispersion at the RV and left ventricle were increased at 6 months. Intraventricular conduction was delayed only in the RV at 6 months (1.8 ± 0.2 and 2.4 ± 0.6 m/s for group 6M and the control group; P = 0.035). Sustained ventricular arrhythmias were not inducible. CONCLUSIONS: In animals yielding the sequelae of a contemporary operation for TOF, mechano-electrical alterations are progressive and affect predominantly the RV after midterm exposure of PR. Because ventricular arrhythmias were not inducible despite significant RV dilation, the data suggest that the haemodynamic RV deterioration effectively precedes the risk of inducing sustained arrhythmia after TOF repair and opens a window for renewed stratification of contemporary risk factors of ventricular arrhythmias in patients operated on with currently used pulmonary valve- and RV-related techniques.

Development of a Novel Risk Prediction Model for Sudden Cardiac Death in Childhood Hypertrophic Cardiomyopathy (HCM Risk-Kids).

Importance: Sudden cardiac death (SCD) is the most common mode of death in childhood hypertrophic cardiomyopathy (HCM), but there is no validated algorithm to identify those at highest risk. Objective: To develop and validate an SCD risk prediction model that provides individualized risk estimates. Design, Setting, and Participants: A prognostic model was developed from a retrospective, multicenter, longitudinal cohort study of 1024 consecutively evaluated patients aged 16 years or younger with HCM. The study was conducted from January 1, 1970, to December 31, 2017. Exposures: The model was developed using preselected predictor variables (unexplained syncope, maximal left-ventricular wall thickness, left atrial diameter, left-ventricular outflow tract gradient, and nonsustained ventricular tachycardia) identified from the literature and internally validated using bootstrapping. Main Outcomes and Measures: A composite outcome of SCD or an equivalent event (aborted cardiac arrest, appropriate implantable cardioverter defibrillator therapy, or sustained ventricular tachycardia associated with hemodynamic compromise). Results: Of the 1024 patients included in the study, 699 were boys (68.3%); mean (interquartile range [IQR]) age was 11 (7-14) years. Over a median follow-up of 5.3 years (IQR, 2.6-8.3; total patient years, 5984), 89 patients (8.7%) died suddenly or had an equivalent event (annual event rate, 1.49; 95% CI, 1.15-1.92). The pediatric model was developed using preselected variables to predict the risk of SCD. The model's ability to predict risk at 5 years was validated; the C statistic was 0.69 (95% CI, 0.66-0.72), and the calibration slope was 0.98 (95% CI, 0.59-1.38). For every 10 implantable cardioverter defibrillators implanted in patients with 6% or more of a 5-year SCD risk, 1 patient may potentially be saved from SCD at 5 years. Conclusions and Relevance: This new, validated risk stratification model for SCD in childhood HCM may provide individualized estimates of risk at 5 years using readily obtained clinical risk factors. External validation studies are required to demonstrate the accuracy of this model's predictions in diverse patient populations.

Sleep apnea and the impact on cardiovascular risk in patients with Marfan syndrome.

BACKGROUND: Marfan syndrome (MFS) is an inherited connective tissue disorder characterized by ectopia lentis, aortic root dilation and dissection and specific skeletal features. Obstructive sleep apnea (OSA) in MFS has been described earlier but the prevalence and its relation with the cardiovascular risk is still controversial. This study aimed to further investigate these aspects. METHODS: In this prospective longitudinal study, we performed an attended polysomnography in 40 MFS patients (60% women, 37 ± 12.8 years) and evaluated several cardiovascular parameters through echocardiography, resting electrocardiogram, 24 hr-Holter monitoring and serum NT-ProBNP measurements. RESULTS: We found that OSA was present in 42.5% of the patients and that higher body mass index was the most important factor associated with the presence of OSA. We observed that overweight was present in 27.5% of the patients in the whole cohort and in 55.6% if >40 years. Furthermore, when evaluating the impact of OSA on the cardiovascular system, we observed that patients with OSA tended to have higher systolic blood pressure, larger distal aortic diameters and a higher prevalence of ventricular arrhythmia. These differences were, however, not significant after adjusting for confounders. CONCLUSIONS: Our study shows a high prevalence of OSA and a high prevalence of overweight in MFS patients. We found some trends between OSA and cardiovascular features but we could not establish a solid association. Our study, however might be underpowered, and a multicenter collaborative study could be very useful to answer some important open questions.

Differences in cerebral and muscle oxygenation patterns during exercise in children with univentricular heart after Fontan operation compared to healthy peers.

BACKGROUND: We assess whether the lower exercise tolerance in children with univentricular heart (UVH) after Fontan operation is associated with altered peripheral muscular and cerebral tissue oxygenation. METHODS: 18 children with UVH and 20 healthy subjects performed an incremental ramp exercise test. Changes in the cerebral and muscular pattern of oxygenated (O2Hb) and deoxygenated hemoglobin (HHb) and local tissue oxygenation (TOI) were analyzed by means of Near Infrared Spectroscopy (NIRS). Correlations between arterial saturation during exercise and tissue oxygenation were evaluated. RESULTS: In UVH, maximal oxygen consumption (VO2peak/kg, 28.9 ±â€¯7.9 vs. 46.3 ±â€¯11.9 ml/min/kg, P < 0.001), heart rate (HRpeak, 168 ±â€¯13 vs. 193 ±â€¯12 bpm, P < 0.001) and load (Ppeak, 73 ±â€¯19 vs. 133 ±â€¯68 W, P < 0.001) were lower, VE/VCO2 slope was higher (34.5 ±â€¯5.9 vs. 27.1 ±â€¯3.9, P < 0.001). A faster and steeper course up to the same level of HHb and absent increase in O2Hb was seen at cerebral level in UVH; tissue oxygenation index (TOI) demonstrated a steady decrease from the start of exercise. At the muscular level, HHb curve has a similar pattern compared to controls, with an early cessation. O2Hb has a similar pattern, but with early discontinuation at a higher O2Hb-level. Muscular TOI has the same course throughout exercise, starting from a lower level. Lower arterial saturation and higher age correlated with lower VO2peak; higher amplitude of muscular TOI and lower amplitude cerebral TOI correlated with higher VO2peak. CONCLUSION: Children after Fontan procedure have different oxygenation mechanisms at muscular and cerebral level. This reflects a different balance between O2 supply to O2 demand which might contribute to the reduced exercise tolerance in this patient population.

Different Patterns of Cerebral and Muscular Tissue Oxygenation 10 Years After Coarctation Repair.

The purpose of this study was to assess whether the lower exercise tolerance in children after coarctation repair is associated with alterations in peripheral tissue oxygenation during exercise. A total of 16 children after coarctation repair and 20 healthy control subjects performed an incremental ramp exercise test to exhaustion. Cerebral and locomotor muscle oxygenation were measured by means of near infrared spectroscopy. The responses of cerebral and muscle tissue oxygenation index (cTOI, mTOI), oxygenated (O2Hb), and deoxygenated hemoglobin (HHb) as a function of work rate were compared. Correlations between residual continuous wave Doppler gradients at rest, arm-leg blood pressure difference and local oxygenation responses were evaluated. Age, length, and weight was similar in both groups. Patients with aortic coarctation had lower peak power output (Ppeak) (72.3 ± 20.2% vs. 106 ± 18.7%, P < 0.001), VO2peak/kg (37.3 ± 9.1 vs. 44.2 ± 7.6 ml/kg, P = 0.019) and %VO2peak/kg (85.7 ± 21.9% vs. 112.1 ± 15.5%, P < 0.001). Cerebral O2Hb and HHb had a lower increase in patients vs. controls during exercise, with significant differences from 60 to 90% Ppeak (O2Hb) and 70% to 100% Ppeak (HHb). Muscle TOI was significantly lower in patients from 10 to 70% Ppeak and muscle HHb was significantly higher in patients vs. controls from 20 to 80% Ppeak. Muscle O2Hb was not different between both groups. There was a significant correlation between residual resting blood pressure gradient and Δmuscle HHb/ΔP at 10-20W and 20-30W (r = 0.40, P = 0.039 and r = 0.43, P = 0.034). Children after coarctation repair have different oxygenation responses at muscular and cerebral level. This reflects a different balance between O2 supply to O2 demand which might contribute to the reduced exercise tolerance in this patient population.

Small-sized conduits in the right ventricular outflow tract in young children: bicuspidalized homografts are a good alternative to standard conduits.

OBJECTIVES: Downsizing a homograft (HG) through bicuspidalization has been used for more than 2 decades to overcome the shortage of small-sized conduits for reconstruction of the right ventricular outflow tract (RVOT) in young children. Our goal was to investigate the durability of bicuspidalized HGs compared with other small HGs. METHODS: A retrospective analysis of 93 conduits ≤20 mm, implanted over 23 years, was performed. The end-points were survival, structural valve degeneration and conduit replacement. The conduits comprised 40 pulmonary HGs, 12 aortic HGs, 17 bicuspidalized HGs and 24 xenografts. RESULTS: The median age, mean conduit diameter and z-value at implantation were 1.4 (interquartile range 0.3-3) years, 16.5 ± 2.7 mm and 2.8 ± 1.3, respectively. Valve position was heterotopic in 59 patients and orthotopic in 34 patients. At a mean follow-up period of 7.6 ± 5.9 years, the hospital survival rate was 89%. Freedom from explant at 5 and 10 years was 83 ± 5% and 52 ± 6%, respectively. Freedom from structural valve degeneration was 79 ± 5% at 5 years and 47 ± 6% at 10 years [68 ± 8% for pulmonary HG, 42 ± 16% for bicuspidalized HG, 31 ± 15% for aortic HG and 20 ± 9% for xenografts (log rank P < 0.001)]. Multivariable analysis indicated an increased risk for structural valve degeneration with smaller conduit size (hazard ratio 0.79, 95% confidence interval 0.67-0.94; P < 0.008), extra-anatomic position (hazard ratio 2.71, 95% confidence interval 1.33-5.50; P = 0.006) and the use of xenografts compared with non-downsized pulmonary HGs (hazard ratio 4.90, 95% confidence interval 2.23-10.76; P < 0.001). CONCLUSIONS: Appropriately sized pulmonary HGs remain the most durable option for a right ventricular outflow tract conduit in young children. However, when a small pulmonary HG is unavailable, bicuspidalization offers a valid alternative, preferable to xenograft conduits, at mid-term follow-up.

Outcome after prenatal and postnatal diagnosis of complex congenital heart defects and the influence of genetic anomalies.

OBJECTIVE: Determine prenatal detection rate, mortality and association with genetic abnormalities in patients with severe CHD. METHOD: Single center retrospective study in patients with severe CHD diagnosed prenatally or postnatally (2006 to 2014). RESULTS: A total of 567 patients were included, 176 (31%) after prenatal diagnosis, with large differences in prenatal detection rate among CHD types. Coarctation (24%), tetralogy of Fallot (21%) and univentricular heart (19%) were the most prevalent CHD. Overall mortality rate was 30% with important contributions of prenatal mortality including termination of pregnancy (40%) and postnatal compassionate care (15%). In the group requiring surgery, mortality rate was 12%. Genetic testing was available in 70%. A genetic cause was present in 140/394 patients tested (36%; 25% in the total group). Mortality was higher in the group with abnormal genetic testing compared with those with normal or no genetic testing (57/141 vs 112/423; p = 0,002). CONCLUSION: Only one third of severe CHD are detected; overall mortality remains high (30%) with major contributions of termination of pregnancy and compassionate care. A genetic cause was found in 36% and was associated with a decreased survival. Counseling must include the possibility of associated genetic pathology and its impact on survival. © 2017 John Wiley & Sons, Ltd.

Early-onset primary antibody deficiency resembling common variable immunodeficiency challenges the diagnosis of Wiedeman-Steiner and Roifman syndromes.

Syndromic primary immunodeficiencies are rare genetic disorders that affect both the immune system and other organ systems. More often, the immune defect is not the major clinical problem and is sometimes only recognized after a diagnosis has been made based on extra-immunological abnormalities. Here, we report two sibling pairs with syndromic primary immunodeficiencies that exceptionally presented with a phenotype resembling early-onset common variable immunodeficiency, while extra-immunological characteristics were not apparent at that time. Additional features not typically associated with common variable immunodeficiency were diagnosed only later, including skeletal and organ anomalies and mild facial dysmorphism. Whole exome sequencing revealed KMT2A-associated Wiedemann-Steiner syndrome in one sibling pair and their mother. In the other sibling pair, targeted testing of the known disease gene for Roifman syndrome (RNU4ATAC) provided a definite diagnosis. With this study, we underline the importance of an early-stage and thorough genetic assessment in paediatric patients with a common variable immunodeficiency phenotype, to establish a conclusive diagnosis and guide patient management. In addition, this study extends the mutational and immunophenotypical spectrum of Wiedemann-Steiner and Roifman syndromes and highlights potential directions for future pathophysiological research.

Early and late outcomes after surgical management of congenital vascular rings.

Persistent respiratory or feeding problems in children may be associated with a congenital vascular ring. Surgical management is fairly standardized, but long-term outcomes are not well described. This study aims to investigate clinical presentation, surgical treatment, and risk factors for early mortality and late outcome. Our database revealed 62 surgically treated vascular ring patients between 1993 and 2014. Double aortic arch was the most common diagnosis (53%). Median age at operation was 1 year. Symptoms were mainly respiratory (89%) and feeding problems (32%). Median extubation time and hospital stay were 4 h and 5 days. Mean follow-up was 7.8 ± 5.8 years. Early mortality was 8% and was related to anatomical diagnosis, concomitant anomalies, and a need for preoperative intubation. Freedom from residual symptoms at 1 and 6 months was 63 and 82%, respectively. Freedom from inhalation therapy at the last follow-up was 82% and was influenced by a type of vascular ring and preoperative ventilation. Dysphagia symptoms always disappeared. CONCLUSION: Surgical relief of tracheoesophageal compression is commonly effective in vascular ring anomalies. Respiratory symptoms necessitating chronic inhalation therapy only persist in a minority of children. Patients with double aortic arch are at increased risk to remain symptomatic, particularly with infectious exacerbations.

Increased aortic stiffness in prepubertal girls with Turner syndrome.

BACKGROUND: Aortic dilation and dissection contribute highly to the increased mortality of Turner syndrome (TS) but the exact pathophysiology is not completely understood. DESIGN: Prospective case - control study. METHODS: 15 prepubertal TS girls (median age 10.64, IQ 8.31-11.04) with a tricuspid (TAV, n=9) or a bicuspid (BAV, n=6) aortic valve, and 31 sex-, age-, and height-matched healthy controls underwent a cardiac and vascular ultrasound to evaluate aortic dimensions and elastic properties of the aortic wall. RESULTS: TS BAV had significantly larger ascending aortic diameters than controls for absolute diameter, 22.2±5.1mm vs. 18.6±1.9mm (p=0.014) and z-score 1.7±2.1 vs. 0.1±0.7 (p=0.008). Distensibility of the ascending aorta was lower in the TS than in controls (40.2×10-3kPa-1, IQ 31.3-56.2 vs. 62.9×10-3kPa-1, IQ 55.5-76.5, p=0.003), both for TS TAV (p=0.014) and BAV (p=0.005). Stiffness index was higher in TS than in controls (5.26, IQ 3.34-5.26 vs. 3.23, IQ 2.55-3.24, p=0.005), both for TS TAV (p=0.028) and TS BAV (p=0.006). Pulse wave velocity was not different between groups. There was no correlation between stiffness and z-score of the ascending aortic diameter. CONCLUSIONS: In prepubertal TS girls, stiffness of the ascending aorta is increased in patients with a BAV and TAV while dilation of the ascending aorta is more frequent in BAV. This suggests an intrinsic aortic wall abnormality making all TS patients at increased risk for severe aortic complications although the risk is the highest for TS with BAV.