Natural history and outcomes in paediatric RASopathy-associated hypertrophic cardiomyopathy.

AIMS: This study aimed to describe the natural history and predictors of all-cause mortality and sudden cardiac death (SCD)/equivalent events in children with a RASopathy syndrome and hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: This is a retrospective cohort study from 14 paediatric cardiology centres in the United Kingdom and Ireland. We included children <18 years with HCM and a clinical and/or genetic diagnosis of a RASopathy syndrome [Noonan syndrome (NS), NS with multiple lentigines (NSML), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFCS), and NS with loose anagen hair (NS-LAH)]. One hundred forty-nine patients were recruited [111 (74.5%) NS, 12 (8.05%) NSML, 6 (4.03%) CS, 6 (4.03%) CFCS, 11 (7.4%) Noonan-like syndrome, and 3 (2%) NS-LAH]. NSML patients had higher left ventricular outflow tract (LVOT) gradient values [60 (36-80) mmHg, P = 0.004]. Over a median follow-up of 197.5 [inter-quartile range (IQR) 93.58-370] months, 23 patients (15.43%) died at a median age of 24.1 (IQR 5.6-175.9) months. Survival was 96.45% [95% confidence interval (CI) 91.69-98.51], 90.42% (95% CI 84.04-94.33), and 84.12% (95% CI 75.42-89.94) at 1, 5, and 10 years, respectively, but this varied by RASopathy syndrome. RASopathy syndrome, symptoms at baseline, congestive cardiac failure (CCF), non-sustained ventricular tachycardia (NSVT), and maximal left ventricular wall thickness were identified as predictors of all-cause mortality on univariate analysis, and CCF, NSVT, and LVOT gradient were predictors for SCD or equivalent event. CONCLUSIONS: These findings highlight a distinct category of patients with Noonan-like syndrome with a milder HCM phenotype but significantly worse survival and identify potential predictors of adverse outcome in patients with RASopathy-related HCM.

Sudden cardiac death in childhood RASopathy-associated hypertrophic cardiomyopathy: Validation of the HCM risk-kids model and predictors of events.

BACKGROUND: RASopathies account for nearly 20% of cases of childhood hypertrophic cardiomyopathy (HCM). Sudden cardiac death (SCD) occurs in patients with RASopathy-associated HCM, but the risk factors for SCD have not been systematically evaluated. AIM: To validate the HCM Risk-Kids SCD risk prediction model in children with RASopathy-associated HCM and investigate potential specific SCD predictors in this population. METHODS: Validation of HCM Risk-Kids was performed in a retrospective cohort of 169 patients with a RASopathy-associated HCM from 15 international paediatric cardiology centres. Multiple imputation by chained equations was used for missing values related to the HCM Risk-Kids parameters. RESULTS: Eleven patients (6.5%) experienced a SCD or equivalent event at a median age of 12.5 months (IQR 7.7-28.64). The calculated SCD/equivalent event incidence was 0.78 (95% CI 0.43-1.41) per 100 patient years. Six patients (54.54%) with an event were in the low-risk category according to the HCM Risk-Kids model. Harrell's C index was 0.60, with a sensitivity of 9.09%, specificity of 63.92%, positive predictive value of 1.72%, and negative predictive value of 91%; with a poor distinction between the different risk groups. Unexplained syncope (HR 42.17, 95% CI 10.49-169.56, p < 0.001) and non-sustained ventricular tachycardia (HR 5.48, 95% CI 1.58-19.03, p < 0.007) were predictors of SCD on univariate analysis. CONCLUSION: Unexplained syncope and the presence of NSVT emerge as predictors for SCD in children with RASopathy-associated HCM. The HCM Risk-Kids model may not be appropriate to use in this population, but larger multicentre collaborative studies are required to investigate this further.

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.

The role of the electrocardiographic phenotype in risk stratification for sudden cardiac death in childhood hypertrophic cardiomyopathy.

AIMS: The 12-lead electrocardiogram (ECG) is routinely performed in children with hypertrophic cardiomyopathy (HCM). An ECG risk score has been suggested as a useful tool for risk stratification, but this has not been independently validated. This aim of this study was to describe the ECG phenotype of childhood HCM in a large, international, multi-centre cohort and investigate its role in risk prediction for arrhythmic events. METHODS AND RESULTS: Data from 356 childhood HCM patients with a mean age of 10.1 years (±4.5) were collected from a retrospective, multi-centre international cohort. Three hundred and forty-seven (97.5%) patients had ECG abnormalities at baseline, most commonly repolarization abnormalities (n = 277, 77.8%); left ventricular hypertrophy (n = 240, 67.7%); abnormal QRS axis (n = 126, 35.4%); or QT prolongation (n = 131, 36.8%). Over a median follow-up of 3.9 years (interquartile range 2.0-7.7), 25 (7%) had an arrhythmic event, with an overall annual event rate of 1.38 (95% CI 0.93-2.04). No ECG variables were associated with 5-year arrhythmic event on univariable or multivariable analysis. The ECG risk score threshold of >5 had modest discriminatory ability [C-index 0.60 (95% CI 0.484-0.715)], with corresponding negative and positive predictive values of 96.7% and 6.7. CONCLUSION: In a large, international, multi-centre cohort of childhood HCM, ECG abnormalities were common and varied. No ECG characteristic, either in isolation or combined in the previously described ECG risk score, was associated with 5-year sudden cardiac death risk. This suggests that the role of baseline ECG phenotype in improving risk stratification in childhood HCM is limited.

Friedreich's ataxia-associated childhood hypertrophic cardiomyopathy: a national cohort study.

OBJECTIVE: Hypertrophic cardiomyopathy (HCM) is an important predictor of long-term outcomes in Friedreich's ataxia (FA), but the clinical spectrum and survival in childhood is poorly described. This study aimed to describe the clinical characteristics of children with FA-HCM. DESIGN AND SETTING: Retrospective, longitudinal cohort study of children with FA-HCM from the UK. PATIENTS: 78 children (<18 years) with FA-HCM diagnosed over four decades. INTERVENTION: Anonymised retrospective demographic and clinical data were collected from baseline evaluation and follow-up. MAIN OUTCOME MEASURES: The primary study end-point was all-cause mortality (sudden cardiac death, atrial arrhythmia-related death, heart failure-related death, non-cardiac death) or cardiac transplantation. RESULTS: The mean age at diagnosis of FA-HCM was 10.9 (±3.1) years. Diagnosis was within 1 year of cardiac referral in 34 (65.0%) patients, but preceded the diagnosis of FA in 4 (5.3%). At baseline, 65 (90.3%) had concentric left ventricular hypertrophy and 6 (12.5%) had systolic impairment. Over a median follow-up of 5.1 years (IQR 2.4-7.3), 8 (10.5%) had documented supraventricular arrhythmias and 8 (10.5%) died (atrial arrhythmia-related n=2; heart failure-related n=1; non-cardiac n=2; or unknown cause n=3), but there were no sudden cardiac deaths. Freedom from death or transplantation at 10 years was 80.8% (95% CI 62.5 to 90.8). CONCLUSIONS: This is the largest cohort of childhood FA-HCM reported to date and describes a high prevalence of atrial arrhythmias and impaired systolic function in childhood, suggesting early progression to end-stage disease. Overall mortality is similar to that reported in non-syndromic childhood HCM, but no patients died suddenly.

Clinical presentation and long-term outcomes of infantile hypertrophic cardiomyopathy: a European multicentre study.

AIMS: Children presenting with hypertrophic cardiomyopathy (HCM) in infancy are reported to have a poor prognosis, but this heterogeneous group has not been systematically characterized. This study aimed to describe the aetiology, phenotype, and outcomes of infantile HCM in a well-characterized multicentre European cohort. METHODS AND RESULTS: Of 301 children diagnosed with infantile HCM between 1987 and 2019 presenting to 17 European centres [male n = 187 (62.1%)], underlying aetiology was non-syndromic (n = 138, 45.6%), RASopathy (n = 101, 33.6%), or inborn error of metabolism (IEM) (n = 49, 16.3%). The most common reasons for presentation were symptoms (n = 77, 29.3%), which were more prevalent in those with syndromic disease (n = 62, 61.4%, P < 0.001), and an isolated murmur (n = 75, 28.5%). One hundred and sixty-one (53.5%) had one or more co-morbidities. Genetic testing was performed in 163 (54.2%) patients, with a disease-causing variant identified in 115 (70.6%). Over median follow-up of 4.1 years, 50 (16.6%) underwent one or more surgical interventions; 15 (5.0%) had an arrhythmic event (6 in the first year of life); and 48 (15.9%) died, with an overall 5 year survival of 85%. Predictors of all-cause mortality were an underlying diagnosis of IEM [hazard ratio (HR) 4.4, P = 0.070], cardiac symptoms (HR 3.2, P = 0.005), and impaired left ventricular systolic function (HR 3.0, P = 0.028). CONCLUSIONS: This large, multicentre study of infantile HCM describes a complex cohort of patients with a diverse phenotypic spectrum and clinical course. Although overall outcomes were poor, this was largely related to underlying aetiology emphasizing the importance of comprehensive aetiological investigations, including genetic testing, in infantile HCM.

Clinical outcomes and programming strategies of implantable cardioverter-defibrillator devices in paediatric hypertrophic cardiomyopathy: a UK National Cohort Study.

AIMS: Sudden cardiac death (SCD) is the most common mode of death in paediatric hypertrophic cardiomyopathy (HCM). This study describes the implant and programming strategies with clinical outcomes following implantable cardioverter-defibrillator (ICD) insertion in a well-characterized national paediatric HCM cohort. METHODS AND RESULTS: Data from 90 patients undergoing ICD insertion at a median age 13 (±3.5) for primary (n = 67, 74%) or secondary prevention (n = 23, 26%) were collected from a retrospective, longitudinal multi-centre cohort of children (<16 years) with HCM from the UK. Seventy-six (84%) had an endovascular system [14 (18%) dual coil], 3 (3%) epicardial, and 11 (12%) subcutaneous system. Defibrillation threshold (DFT) testing was performed at implant in 68 (76%). Inadequate DFT in four led to implant adjustment in three patients. Over a median follow-up of 54 months (interquartile range 28-111), 25 (28%) patients had 53 appropriate therapies [ICD shock n = 45, anti-tachycardia pacing (ATP) n = 8], incidence rate 4.7 per 100 patient years (95% CI 2.9-7.6). Eight inappropriate therapies occurred in 7 (8%) patients (ICD shock n = 4, ATP n = 4), incidence rate 1.1/100 patient years (95% CI 0.4-2.5). Three patients (3%) died following arrhythmic events, despite a functioning device. Other device complications were seen in 28 patients (31%), including lead-related complications (n = 15) and infection (n = 10). No clinical, device, or programming characteristics predicted time to inappropriate therapy or lead complication. CONCLUSION: In a large national cohort of paediatric HCM patients with an ICD, device and programming strategies varied widely. No particular strategy was associated with inappropriate therapies, missed/delayed therapies, or lead complications.

Prenatal and Postnatal Cardiac Development in Offspring of Hypertensive Pregnancies.

Background Pregnancy complications such as preterm birth and fetal growth restriction are associated with altered prenatal and postnatal cardiac development. We studied whether there were changes related specifically to pregnancy hypertension. Methods and Results Left and right ventricular volumes, mass, and function were assessed at birth and 3 months of age by echocardiography in 134 term-born infants. Fifty-four had been born to mothers who had normotensive pregnancy and 80 had a diagnosis of preeclampsia or pregnancy-induced hypertension. Differences between groups were interpreted, taking into account severity of pregnancy disorder, sex, body size, and blood pressure. Left and right ventricular mass indexed to body surface area (LVMI and RVMI) were similar in both groups at birth (LVMI 20.9±3.7 versus 20.6±4.0 g/m2, P=0.64, RVMI 17.5±3.7 versus 18.1±4.7 g/m2, P=0.57). However, right ventricular end diastolic volume index was significantly smaller in those born to hypertensive pregnancy (16.8±5.3 versus 12.7±4.7 mL/m2, P=0.001), persisting at 3 months of age (16.4±3.2 versus 14.4±4.8 mL/m2, P=0.04). By 3 months of age these infants also had significantly greater LVMI and RVMI (LVMI 24.9±4.6 versus 26.8±4.9 g/m2, P=0.04; RVMI 17.1±4.2 versus 21.1±3.9 g/m2, P<0.001). Differences in RVMI and right ventricular end diastolic volume index at 3 months, but not left ventricular measures, correlated with severity of the hypertensive disorder. No differences in systolic or diastolic function were evident. Conclusions Infants born at term to a hypertensive pregnancy have evidence of both prenatal and postnatal differences in cardiac development, with right ventricular changes proportional to the severity of the pregnancy disorder. Whether differences persist long term as well as their underlying cause and relationship to increased cardiovascular risk requires further study.

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.

A validation study of the European Society of Cardiology guidelines for risk stratification of sudden cardiac death in childhood hypertrophic cardiomyopathy.

AIMS: Sudden cardiac death (SCD) is the most common cause of death in children with hypertrophic cardiomyopathy (HCM). The European Society of Cardiology (ESC) recommends consideration of an implantable cardioverter-defibrillator (ICD) if two or more clinical risk factors (RFs) are present, but this approach to risk stratification has not been formally validated. METHODS AND RESULTS: Four hundred and eleven paediatric HCM patients were assessed for four clinical RFs in accordance with current ESC recommendations: severe left ventricular hypertrophy, unexplained syncope, non-sustained ventricular tachycardia, and family history of SCD. The primary endpoint was a composite outcome of SCD or an equivalent event (aborted cardiac arrest, appropriate ICD therapy, or sustained ventricular tachycardia), defined as a major arrhythmic cardiac event (MACE). Over a follow-up period of 2890 patient years (median 5.5 years), MACE occurred in 21 patients (7.5%) with 0 RFs, 19 (16.8%) with 1 RFs, and 3 (18.8%) with 2 or more RFs. Corresponding incidence rates were 1.13 [95% confidence interval (CI) 0.7-1.73], 2.07 (95% CI 1.25-3.23), and 2.52 (95% CI 0.53-7.35) per 100 patient years at risk. Patients with two or more RFs did not have a higher incidence of MACE (log-rank test P = 0.34), with a positive and negative predictive value of 19% and 90%, respectively. The C-statistic was 0.62 (95% CI 0.52-0.72) at 5 years. CONCLUSIONS: The incidence of MACE is higher for patients with increasing numbers of clinical RFs. However, the current ESC guidelines have a low ability to discriminate between high- and low-risk individuals.

Clinical presentation and survival of childhood hypertrophic cardiomyopathy: a retrospective study in United Kingdom.

AIMS: Understanding the spectrum of disease, symptom burden and natural history are essential for the management of children with hypertrophic cardiomyopathy (HCM). The effect of changing screening practices over time has not previously been studied. This study describes the clinical characteristics and outcomes of childhood HCM over four decades in a well-characterized United Kingdom cohort. METHODS AND RESULTS: Six hundred and eighty-seven patients with HCM presented at a median age of 5.2 years (range 0-16). Aetiology was: non-syndromic (n = 433, 63%), RASopathy (n = 126, 18.3%), Friedreich's ataxia (n = 59, 8.6%) or inborn errors of metabolism (IEM) (n = 64, 9%). In infants (n = 159, 23%) underlying aetiology was more commonly a RASopathy (42% vs. 11.2%, P < 0.0001) or IEM (18.9% vs. 6.4% P < 0.0001). In those with familial disease, median age of presentation was higher (11 years vs. 6 years, P < 0.0001), 141 (58%) presented <12 years. Freedom from death or transplantation was 90.6% (87.9-92.7%) at 5 years (1.5 per 100 patient years) with no era effect. Mortality was most frequently sudden cardiac death (SCD) (n = 20, 2.9%). Children diagnosed during infancy or with an IEM had a worse prognosis (5-year survival 80.5% or 66.4%). Arrhythmic events occurred at a rate of 1.2 per 100 patient years and were more likely in non-syndromic patients (n = 51, 88%). CONCLUSION: This national study describes a heterogeneous disease whose outcomes depend on the age of presentation and aetiology. Overall mortality and SCD rates have not changed over time, but they remain higher than in adults with HCM, with events occurring in syndromic and non-syndromic patients.

Randomised placebo-controlled trial of combination ACE inhibitor and beta-blocker therapy to prevent cardiomyopathy in children with Duchenne muscular dystrophy? (DMD Heart Protection Study): a protocol study.

INTRODUCTION: Although cardiologists were 'late-comers' to the multidisciplinary team-contributing to the complex care of patients with Duchenne muscular dystrophy (DMD), they now recognise the importance of systematic cardiac surveillance and timely therapy to prolonged survival in patients with DMD. Empirical deployment of cardioactive medications has already improved outcomes, but the evidence base for clinical decision making is weak. Fundamental questions remain as to whether prophylactic therapy is justified and convincingly superior to prompt deployment of the same therapies once left ventricular (LV) dysfunction is detected. Even if it were, at what age should therapy be introduced and with what specific drugs? METHODS AND ANALYSIS: We are conducting a multicentre, parallel group, randomised, placebo-controlled study of combination therapy with an ACE inhibitor (perindopril) and a beta-blocker (bisoprolol) in boys with DMD aged 5-13 years, with normal LV function by echocardiographic criteria at the time of recruitment. Boys are being followed-up for a minimum of 3 years and a maximum of 5 years and undergo repeat assessments of LV function, heart rate and ECG, forced expiratory volume in the 1 s and forced vital capacity, adverse event reporting and quality of life at 6 monthly intervals.The primary outcome is change in LV function between active and placebo-treated participants over the course of the study. ETHICS AND DISSEMINATION: The study was approved by 'NRES Committee East Midlands - Derby'. The results will be disseminated through manuscript publications, an international workshop and presentations to scientific meetings and parent forums. TRANSLATIONAL ASPECTS: The study seeks to establish the evidence for prophylactic heart therapies for children with DMD, define the optimum age for their introduction and identify any safety concerns. ARTICLE SUMMARY: The protocol describes the design of an ongoing multicentre, double-blind, randomised placebo-controlled study to establish the evidence for the use of prophylactic heart therapies in children with DMD, define the optimum age for their introduction and identify any safety concerns. TRIAL REGISTRATION NUMBERS: EudraCT2007-005932-10 and ISRCTN50395346; Pre-results.

Neonatal autonomic function after pregnancy complications and early cardiovascular development.

BACKGROUND: Heart rate variability (HRV) has emerged as a predictor of later cardiac risk. This study tested whether pregnancy complications that may have long-term offspring cardiac sequelae are associated with differences in HRV at birth, and whether these HRV differences identify abnormal cardiovascular development in the postnatal period. METHODS: Ninety-eight sleeping neonates had 5-min electrocardiogram recordings at birth. Standard time and frequency domain parameters were calculated and related to cardiovascular measures at birth and 3 months of age. RESULTS: Increasing prematurity, but not maternal hypertension or growth restriction, was associated with decreased HRV at birth, as demonstrated by a lower root mean square of the difference between adjacent NN intervals (rMSSD) and low (LF) and high-frequency power (HF), with decreasing gestational age (p < 0.001, p = 0.009 and p = 0.007, respectively). We also demonstrated a relative imbalance between sympathetic and parasympathetic tone, compared to the term infants. However, differences in autonomic function did not predict cardiovascular measures at either time point. CONCLUSIONS: Altered cardiac autonomic function at birth relates to prematurity rather than other pregnancy complications and does not predict cardiovascular developmental patterns during the first 3 months post birth. Long-term studies will be needed to understand the relevance to cardiovascular risk.

Outcome after transcatheter occlusion of patent ductus arteriosus in infants less than 6 kg: A national study from United Kingdom and Ireland.

OBJECTIVES: This study aimed to report our national experience with transcatheter patent ductus arteriosus (PDA) occlusion in infants weighing <6 kg. BACKGROUND: The technique of transcatheter PDA closure has evolved in the past two decades and is increasingly used in smaller patients but data on safety and efficacy are limited. METHODS: Patients weighing < 6 kg in whom transcatheter PDA occlusion was attempted in 13 tertiary paediatric cardiology units in the United Kingdom and Ireland were retrospectively analyzed to review the outcome and complications. RESULTS: A total of 408 patients underwent attempted transcatheter PDA closure between January 2004 and December 2014. The mean weight at catheterization was 4.9 ± 1.0 kg and mean age was 5.7 ± 3.0 months. Successful device implantation was achieved in 374 (92%) patients without major complication and of these, complete occlusion was achieved in 356 (95%) patients at last available follow-up. Device embolization occurred in 20 cases (5%). The incidence of device related obstruction to the left pulmonary artery or aorta and access related peripheral vascular injury were low. There were no deaths related to the procedure. CONCLUSIONS: Transcatheter closure of PDA can be accomplished in selected infants weighing <6 kg despite the manufacturer's recommended weight limit of 6 kg for most ductal occluders. The embolization rate is higher than previously reported in larger patients. Retrievability of the occluder and duct morphology needs careful consideration before deciding whether surgical ligation or transcatheter therapy is the better treatment option.

Disproportionate cardiac hypertrophy during early postnatal development in infants born preterm.

BackgroundAdults born very preterm have increased cardiac mass and reduced function. We investigated whether a hypertrophic phenomenon occurs in later preterm infants and when this occurs during early development.MethodsCardiac ultrasound was performed on 392 infants (33% preterm at mean gestation 34±2 weeks). Scans were performed during fetal development in 137, at birth and 3 months of postnatal age in 200, and during both fetal and postnatal development in 55. Cardiac morphology and function was quantified and computational models created to identify geometric changes.ResultsAt birth, preterm offspring had reduced cardiac mass and volume relative to body size with a more globular heart. By 3 months, ventricular shape had normalized but both left and right ventricular mass relative to body size were significantly higher than expected for postmenstrual age (left 57.8±41.9 vs. 27.3±29.4%, P<0.001; right 39.3±38.1 vs. 16.6±40.8, P=0.002). Greater changes were associated with lower gestational age at birth (left P<0.001; right P=0.001).ConclusionPreterm offspring, including those born in late gestation, have a disproportionate increase in ventricular mass from birth up to 3 months of postnatal age. These differences were not present before birth. Early postnatal development may provide a window for interventions relevant to long-term cardiovascular health.

A Case of Neonatal Marfan Syndrome: A Management Conundrum and the Role of a Multidisciplinary Team.

Neonatal Marfan syndrome (nMFS) is a rare condition with a poor prognosis. It is genotypically and phenotypically distinct from the typical Marfan syndrome and carries a poorer prognosis. This case report describes the progression of a 14-month-old girl diagnosed with nMFS at 5 months of age. Her diagnosis followed the identification of a fibrillin-1 mutation (FBN1 gene, exon 26, chromosome 15), which is a common locus of nMFS. This patient developed severe cardiac complications resulting in congestive cardiac failure in early life and required major cardiac surgery. Since surgical intervention, our patient is still reliant on a degree of ventilator support, but the patient has gained weight and echocardiography has demonstrated improved left ventricular function and improved tricuspid and mitral valve regurgitation. Therefore, we argue the importance of a cautious multidisciplinary approach to early surgical intervention in cases of nMFS.

Down syndrome masked by Marfan syndrome in a neonate.

A male neonate with maternally inherited Marfan syndrome was also diagnosed with Down syndrome at 3 weeks of age. To our knowledge this is the first described case in the literature of the co-occurrence of Down syndrome and Marfan syndrome in a neonate. The diagnosis of Down syndrome was delayed and we hypothesise that Marfan syndrome had masked the usual phenotypic features of Down syndrome. The phenotype of this child is intriguing and has lead to speculation of the possible interaction of the two syndromes.

Cardiovascular risk factors in children and young adults born to preeclamptic pregnancies: a systematic review.

BACKGROUND AND OBJECTIVE: Preeclampsia is an independent cardiovascular risk factor for the mother, and recent studies reveal that offspring of affected pregnancies also may have an increased cardiovascular risk. Our objective was to examine evidence for increased cardiovascular risk factors in children exposed to preeclampsia in utero. METHODS: We performed a systematic review and meta-analysis on studies reporting traditional cardiovascular risk factors in those exposed to preeclampsia compared to controls. Information was extracted on the classic cardiovascular risk factors, including blood pressure, lipid profile, glucose metabolism, and BMI from articles published between 1948 and August 2011 in Medline and Embase. RESULTS: Eighteen studies provided cumulated data on 45,249 individuals. In utero exposure to preeclampsia was associated with a 2.39 mm Hg (95% confidence interval: 1.74-3.05; P < .0001) higher systolic and a 1.35 mm Hg (95% confidence interval: 0.90-1.80; P < .00001) higher diastolic blood pressure during childhood and young adulthood. BMI was increased by 0.62 kg/m2 (P < .00001). Associations were similar in children and adolescents, for different genders, and with variation in birth weight. There was insufficient evidence to identify consistent variation in lipid profile or glucose metabolism. CONCLUSIONS: Young offspring of pregnancies complicated by preeclampsia already have increased blood pressure and BMI, a finding that may need to be considered in future primary prevention strategies for cardiovascular disease.