Expanding the phenotypic spectrum of NOTCH1 variants: clinical manifestations in families with congenital heart disease.

Pathogenic variants in NOTCH1 are associated with non-syndromic congenital heart disease (CHD) and Adams-Oliver syndrome (AOS). The clinical presentation of individuals with damaging NOTCH1 variants is characterized by variable expressivity and incomplete penetrance; however, data on systematic phenotypic characterization are limited. We report the genotype and phenotype of a cohort of 33 individuals (20 females, 13 males; median age 23.4 years, range 2.5-68.3 years) from 11 families with causative NOTCH1 variants (9 inherited, 2 de novo; 9 novel), ascertained from a proband with CHD. We describe the cardiac and extracardiac anomalies identified in these 33 individuals, only four of whom met criteria for AOS. The most common CHD identified was tetralogy of Fallot, though various left- and right-sided lesions and septal defects were also present. Extracardiac anomalies identified include cutis aplasia (5/33), cutaneous vascular anomalies (7/33), vascular anomalies of the central nervous system (2/10), Poland anomaly (1/33), pulmonary hypertension (2/33), and structural brain anomalies (3/14). Identification of these findings in a cardiac proband cohort supports NOTCH1-associated CHD and NOTCH1-associated AOS lying on a phenotypic continuum. Our findings also support (1) Broad indications for NOTCH1 molecular testing (any familial CHD, simplex tetralogy of Fallot or hypoplastic left heart); (2) Cascade testing in all at-risk relatives; and (3) A thorough physical exam, in addition to cardiac, brain (structural and vascular), abdominal, and ophthalmologic imaging, in all gene-positive individuals. This information is important for guiding the medical management of these individuals, particularly given the high prevalence of NOTCH1 variants in the CHD population.

Coronary artery lesions are associated with adverse cardiac events in children undergoing supravalvular aortic stenosis repair.

OBJECTIVES: The aim of this study was to identify the prevalence and anatomic characteristics of coronary artery lesions and their associated postoperative risk in patients undergoing supravalvular aortic stenosis repair. METHODS: The association between structural risk factors, postoperative ST-segment changes, and major adverse cardiac events was explored using logistic regression and the Fisher's exact test. RESULTS: In 51 consecutive patients with supravalvular aortic stenosis treated between 2000 and 2017, a total of 48 coronary lesions were identified in 27 patients (53%). Prominent ostial ridge (type I) was the most common coronary lesion, followed by small ostium with (IIIb) or without (IIIa) diffuse long-segment coronary narrowing, and adhesion of the coronary cusp (type II). There were 54 concomitant coronary procedures, including 43 primary corrections and 11 revisions. Thirty-three patients underwent supravalvular aortic stenosis repair with a bifurcated patch, of which 13 (39.4%) had right coronary artery distortion/kinking requiring patch plication (n = 8) and reimplantation (n = 5). Postoperative major adverse cardiac events (MACE) occurred in 9 patients (17.6%), including 3 deaths, 4 needing mechanical circulatory support, and 6 experiencing ventricular arrhythmias. Twenty-two patients (43.1%) had postoperative ST-segment changes, including 13 early changes that resolved within 24 h and 9 persistent changes lasting >24 h. Patients with type III lesions were associated with postoperative persistent ST-segment change (P = 0.04) and these lesions independently predicted postoperative MACE (P = 0.02). Patients with pre-existing coronary lesions were at elevated risk of right coronary artery distortion/kinking (P = 0.045). CONCLUSIONS: The prevalence of ST-segment changes and MACE is high in patients undergoing supravalvular aortic stenosis repair. The preoperative presence of complex coronary lesions is the most important predictor for postoperative major adverse cardiac events.

Fetal Cardiology Bioethics: An Innovative New Curriculum for Cardiology Trainees.

Decision-making in fetal cardiology is fraught with ethical issues yet education in bioethics for trainees is limited or nonexistent. In this innovation report, we describe the development of a fetal cardiology bioethics curriculum designed to address this gap. The curriculum was developed to supplement the core curriculum for cardiology fellows and fetal cardiology subspecialty trainees. The series combines didactic and interactive teaching modalities and contains 5 key components: (1) introduction to bioethics and its role in fetal cardiology, (2) counseling and pathways for compassionate terminal care, (3) case vignette-based ethical analysis and discussion cases, (4) fetal counseling considerations for shared decision-making and recommendations, (5) facilitated communications role play. The curriculum was refined using session evaluations from end users. This report describes the innovative curriculum as a starting point for further incorporation and study of bioethical education in pediatric cardiology and fetal training programs.

E-Health: A Game Changer in Fetal and Neonatal Cardiology?

Technological advancements have greatly impacted the healthcare industry, including the integration of e-health in pediatric cardiology. The use of telemedicine, mobile health applications, and electronic health records have demonstrated a significant potential to improve patient outcomes, reduce healthcare costs, and enhance the quality of care. Telemedicine provides a useful tool for remote clinics, follow-up visits, and monitoring for infants with congenital heart disease, while mobile health applications enhance patient and parents' education, medication compliance, and in some instances, remote monitoring of vital signs. Despite the benefits of e-health, there are potential limitations and challenges, such as issues related to availability, cost-effectiveness, data privacy and security, and the potential ethical, legal, and social implications of e-health interventions. In this review, we aim to highlight the current application and perspectives of e-health in the field of fetal and neonatal cardiology, including expert parents' opinions.

The relationships between acetylcholine-induced chest pain, objective measures of coronary vascular function and symptom status.

Background: Acetylcholine-induced chest pain is routinely measured during the assessment of microvascular function. Aims: The aim was to determine the relationships between acetylcholine-induced chest pain and both symptom burden and objective measures of vascular function. Methods: In patients with angina but no obstructive coronary artery disease, invasive studies determined the presence or absence of chest pain during both acetylcholine and adenosine infusion. Thermodilution-derived coronary blood flow (CBF) and index of microvascular resistance (IMR) was determined at rest and during both acetylcholine and adenosine infusion. Patients with epicardial spasm (>90%) were excluded; vasoconstriction between 20% and 90% was considered endothelial dysfunction. Results: Eighty-seven patients met the inclusion criteria. Of these 52 patients (60%) experienced chest pain during acetylcholine while 35 (40%) did not. Those with acetylcholine-induced chest pain demonstrated: (1) Increased CBF at rest (1.6 ± 0.7 vs. 1.2 ± 0.4, p = 0.004) (2) Decreased IMR with acetylcholine (acetylcholine-IMR = 29.7 ± 16.3 vs. 40.4 ± 17.1, p = 0.004), (3) Equivalent IMR following adenosine (Adenosine-IMR: 21.1 ± 10.7 vs. 21.8 ± 8.2, p = 0.76), (4) Increased adenosine-induced chest pain (40/52 = 77% vs. 7/35 = 20%, p < 0.0001), (5) Increased chest pain during exercise testing (30/46 = 63% vs. 4/29 = 12%, p < 0.00001) with no differences in exercise duration or electrocardiographic changes, and (6) Increased prevalence of epicardial endothelial dysfunction (33/52 = 63% vs. 14/35 = 40%, p = 0.03). Conclusions: After excluding epicardial spasm, acetylcholine-induced chest pain is associated with increased pain during exercise and adenosine infusion, increased coronary blood flow at rest, decreased microvascular resistance in response to acetylcholine and increased prevalence of epicardial endothelial dysfunction. These findings raise questions about the mechanisms underlying acetylcholine-induced chest pain.

Competency Standard Derivation for Point-of-Care Ultrasound Image Interpretation for Emergency Physicians.

STUDY OBJECTIVE: Because number-based standards are increasingly controversial, the objective of this study was to derive a performance-based competency standard for the image interpretation task of point-of-care ultrasound (POCUS). METHODS: This was a prospective study. Operating on a clinically-relevant sample of POCUS images, we adapted the Ebel standard-setting method to derive a performance benchmark in 4 diverse pediatric POCUS applications: soft tissue, lung, cardiac and focused assessment with sonography in trauma (FAST). In Phase I (difficulty calibration), cases were categorized into interpretation difficulty terciles (easy, intermediate, hard) using emergency physician-derived data. In Phase II (significance), a 4-person expert panel categorized cases as low, medium, or high clinical significance. In Phase III (standard setting), a 3x3 matrix was created, categorizing cases by difficulty and significance, and a 6-member panel determined acceptable accuracy for each of the 9 cells. An overall competency standard was derived from the weighted sum. RESULTS: We obtained data from 379 emergency physicians resulting in 67,093 interpretations and a median of 184 (interquartile range, 154, 190) interpretations per case. There were 78 (19.5%) easy, 272 (68.0%) medium, and 50 (12.5%) hard-to-interpret cases, and 237 (59.3%) low, 65 (16.3%) medium, and 98 (24.5%) cases of high clinical significance across the 4 POCUS applications. The panel determined an overall performance-based competency score of 85.0% for lung, 89.5% for cardiac, 90.5% for soft tissue, and 92.7% for FAST. CONCLUSION: This research provides a transparent chain of evidence that derived clinically relevant competency standards for POCUS image interpretation.

Comparison of Pre- and Postnatally Diagnosed Coronary Artery Fistulae: Echocardiographic Features and Clinical Outcomes.

BACKGROUND: Coronary artery fistulae (CAFs) are abnormal connections of a coronary artery to a cardiac chamber or vessel. There is a paucity of data regarding clinical outcomes, especially when detected prenatally. METHODS: This was a multicenter retrospective cohort study of all CAF cases from 2002 to 2016. Clinical characteristics and outcomes were compared between the prenatal and postnatal cohorts. A scoping literature review of prenatal CAFs was completed. RESULTS: CAFs were diagnosed prenatally in 12 (median, 23 weeks' gestation; interquartile range, 17-36 weeks' gestation) and postnatally in 94 (median, 2.8 years; interquartile range, 0-15 years) cases. Structural heart defects were present in five (42%) prenatal and 19 (20%) postnatal cases (P = .011) and genetic conditions in five (42%) and 14 (15%), respectively (P = .001). CAFs were considered large in 12 (100%) prenatal versus 14 (15%) postnatal cases (P < .001). The CAF distribution was similar between cohorts: 39 (67%) from the left and 19 (33%) from the right coronary artery, with the most common exit sites being the main pulmonary artery 54 (51%), right ventricle 30 (28%), and right atrium 12 (11%). Of prenatal cases, all large at presentation, none progressed, six (50%) resolved by birth, and one (8%) underwent elective neonatal ligation. Of postnatal cases, one presented in cardiogenic shock, and no other case had ventricular dysfunction, arrhythmias, or ischemic changes. Nine (10%) with large shunts underwent intervention (seven percutaneous, two surgical), of whom three were symptomatic. Two (17%) prenatal and two (2%) postnatal cases had coronary abnormalities, two with normal results on stress perfusion imaging. Postnatal death occurred in two (17%) prenatal and four (4%) postnatal cases (P = .05). Of the total 36 prenatal cases reported in the literature, including the 12 cases in the present series, 10 (28%) had clinical symptoms at birth, including three (8%) with cardiogenic shock, and 19 (53%) underwent intervention. CONCLUSIONS: Prenatally and postnatally encountered CAFs are associated with a good prognosis for most, with many not requiring intervention. Although half of the prenatal CAFs resolved prenatally, given the risk for cardiogenic shock at birth and heart failure in early infancy, appropriate perinatal planning and postnatal surveillance is warranted.

Familial Recurrence Patterns in Congenitally Corrected Transposition of the Great Arteries: An International Study.

BACKGROUND: Congenitally corrected transposition of the great arteries (ccTGA) is a rare disease of unknown cause. We aimed to better understand familial recurrence patterns. METHODS: An international, multicentre, retrospective cohort study was conducted in 29 tertiary hospitals in 6 countries between 1990 and 2018, entailing investigation of 1043 unrelated ccTGA probands. RESULTS: Laterality defects and atrioventricular block at diagnosis were observed in 29.9% and 9.3%, respectively. ccTGA was associated with primary ciliary dyskinesia in 11 patients. Parental consanguinity was noted in 3.4% cases. A congenital heart defect was diagnosed in 81 relatives from 69 families, 58% of them being first-degree relatives, including 28 siblings. The most prevalent defects in relatives were dextro-transposition of the great arteries (28.4%), laterality defects (13.6%), and ccTGA (11.1%); 36 new familial clusters were described, including 8 pedigrees with concordant familial aggregation of ccTGA, 19 pedigrees with familial co-segregation of ccTGA and dextro-transposition of the great arteries, and 9 familial co-segregation of ccTGA and laterality defects. In one family co-segregation of ccTGA, dextro-transposition of the great arteries and heterotaxy syndrome in 3 distinct relatives was found. In another family, twins both displayed ccTGA and primary ciliary dyskinesia. CONCLUSIONS: ccTGA is not always a sporadic congenital heart defect. Familial clusters as well as evidence of an association between ccTGA, dextro-transposition of the great arteries, laterality defects and in some cases primary ciliary dyskinesia, strongly suggest a common pathogenetic pathway involving laterality genes in the pathophysiology of ccTGA.

Concurrently Low Coronary Flow Reserve and Low Index of Microvascular Resistance Are Associated With Elevated Resting Coronary Flow in Patients With Chest Pain and Nonobstructive Coronary Arteries.

BACKGROUND: Coronary microvascular function can be distinctly quantified using the coronary flow reserve (CFR) and index of microvascular resistance (IMR). Patients with low CFR can present with low or high IMR, although the prevalence and clinical characteristics of these patient groups remain unclear. METHODS: One hundred ninety-nine patients underwent coronary microvascular assessments using coronary thermodilution techniques. A pressure-temperature sensor-tipped guidewire measured proximal and distal coronary pressure, whereas the inverse of the mean transit time to room temperature saline was used to measure coronary blood flow. The CFR and IMR were quantified during adenosine and acetylcholine hyperemia. RESULTS: Low adenosine and acetylcholine CFR was observed in 70 and 49 patients, respectively, whereas low CFR/low IMR to adenosine and acetylcholine was observed in 39(56%) and 19(39%) patients, respectively. Despite similar adenosine CFR, patients with low CFR/low IMR had increased resting (2.8±1.2 versus 1.3±0.4s-1) and hyperemic coronary blood flow (4.8±1.5 versus 2.1±0.5s-1) compared with patients with low CFR/high IMR (both P<0.01). The same pattern was observed in response to acetylcholine. Patients with low CFR/low IMR to adenosine were younger (56±12 versus 63±10 years), women (84% versus 66%), had fewer coronary risk factors (1.1±1.0 versus 1.6±1.1), lower hemoglobin A1c (5.8±0.7 versus 6.1±0.9 mmol/L), and thinner septal thickness (8.5±2.5 versus 9.9±1.6 mm) compared with patients with low CFR/high IMR to adenosine (all P<0.05). CONCLUSIONS: Low CFR/low IMR to adenosine and acetylcholine are associated with elevated resting coronary blood flow and preserved hyperemic coronary blood flow. These patients present with distinct phenotypic characteristics. Simultaneous CFR and IMR measures appear necessary to differentiate these endotypes.

Prospective Assessment of Coronary Artery Flows Before and After Cardiopulmonary Bypass in Children With a Spectrum of Congenital Heart Disease.

Background: Normative data for the effect of cardiopulmonary bypass (CPB) on coronary artery Doppler velocities by transesophageal echocardiography in paediatric patients with congenital heart disease (CHD) are lacking. The objective of the study was to prospectively examine the effects of CPB on coronary artery flow patterns by transesophageal echocardiography before and after CPB in children with CHD. Methods: All cases undergoing CHD surgery at the Hospital for Sick Children, Toronto, were eligible. The excluded cases included Norwood operation, heart transplantation, or weight <2.5 kg. Coronary Dopplers and coronary flow reserve (CFR) for the right coronary artery (RCA) and left anterior descending (LAD) were obtained. Multivariable analyses using linear regression models were performed, adjusted for age and cross-clamp time. Results: From May 2017 to June 2018, 69 children (median age at surgery: 0.7 years, interquartile range [IQR]: 0.4-3.7 years; median weight: 7.4 kg, IQR: 5.8-13.3 kg) were included. They were grouped into shunt lesions (N = 26), obstructive lesions (N = 26), transposition of the great arteries (N = 5), and single ventricle (N = 12). N = 39 (57%) were primary repairs, and 56 (81%) had 1 CPB run. For RCA and LAD peak velocities, there was an increase from pre- to post-CPB in RCA peak 39 cm/s (IQR: 30-54 cm/s) to 65 cm/s (IQR: 47-81 cm/s), P < 0.001, mean CFR 1.52 (IQR: 1.25-1.81), and LAD peak 49 cm/s (IQR: 39-60 cm/s) to 70 cm/s (IQR: 52-90 cm/s), P < 0.001, mean CFR 1.48 (IQR: 1.14-1.77). Conclusions: Coronary flow velocities increase from pre- to post-CPB in congenital heart lesions. CFR is consistent across all lesions but is relatively low compared with the adult population.

Contexte: On ne dispose pas de données normatives sur les effets de la dérivation cardiopulmonaire (DCP) sur le débit coronarien mesuré au moyen d'une échocardiographie transœsophagienne Doppler chez des enfants présentant une cardiopathie congénitale. L'objectif de l'étude était d'examiner de manière prospective les effets de la DCP sur le débit coronarien avant et après l'intervention chez des enfants présentant une cardiopathie congénitale. Méthodologie: Tous les enfants ayant subi une intervention chirurgicale pour une cardiopathie congénitale à l'Hospital for Sick Children de Toronto étaient admissibles à l'étude, à l'exception de ceux ayant subi une intervention de Norwood ou une transplantation cardiaque, de même que les enfants pesant moins de 2,5 kg. Les résultats du test Doppler et la réserve coronarienne pour l'artère coronaire droite (ACD) et la branche antérieure de l'artère coronaire gauche (ACG) ont été obtenus. Des analyses multivariées ont été réalisées au moyen de modèles de régression linéaire, avec correction en fonction de l'âge et du temps de clampage total. Résultats: Entre mai 2017 et juin 2018, 69 enfants (âge médian au moment de la chirurgie : 0,7 an, intervalle interquartile (IIQ) : 0,4-3,7 ans; poids médian : 7,4 kg, IIQ : 5,8-13,3 kg) ont été inclus dans l'étude. Les sujets ont été répartis en quatre groupes : shunts (n = 26), lésions obstructives (n = 26), permutation des gros vaisseaux (n = 5) et ventricule unique (n = 12). Chez 39 sujets (57 %), il s'agissait d'une réparation primitive, et 56 enfants (81 %) avaient déjà subi une DCP. Les vitesses maximales dans l'ACD et dans la branche antérieure de l'ACG ont augmenté après la DCP, passant de 39 cm/s (IIQ : 30-54 cm/s) à 65 cm/s (IIQ : 47-81 cm/s), p < 0,001; réserve coronarienne moyenne : 1,52 (IIQ : 1,25-1,81) pour l'ACD, et de 49 cm/s (IIQ : 39-60 cm/s) à 70 cm/s (IIQ : 52-90 cm/s), p < 0,001; réserve coronarienne moyenne : 1,48 (IIQ : 1,14-1,77) pour la branche antérieure de l'ACG. Conclusions: Le débit coronarien augmente après une DCP dans les cas de lésions cardiaques congénitales. La réserve coronarienne est constante dans tous les types de lésions, mais elle est relativement faible comparativement à celle de la population adulte.

Is late treatment with acetaminophen safe and effective in avoiding surgical ligation among extremely preterm neonates with persistent patent ductus arteriosus?

OBJECTIVE: Evaluate the association of late treatment with acetaminophen vs. immediate surgical ligation with death or neurodevelopmental impairment (NDI) among extremely low gestational age neonates (ELGANs) with persistent patent ductus arteriosus (pPDA). STUDY DESIGN: Retrospective comparative epoch study of ELGANs with pPDA being considered for surgical ligation. ELGANs in epoch 1 (2009-2012) were referred for ligation, while infants in epoch 2 (2012-2015) were treated with oral acetaminophen and referred for ligation in the absence of improvement. The primary outcome was a composite of death/NDI at 18-24 months. RESULTS: Ninety-two ELGANs with median[IQR] GA 25.2 weeks [24.4, 26.3] had pPDA (43 in epoch 1, 49 in -epoch 2) with acetaminophen-exposed neonates receiving 7 days [7, 7] of treatment. ELGANs in epoch 2 had reduced ligation (aOR 0.30; 95%CI: [0.11, 0.87]), but there was no difference in death/NDI (aOR 1.03; 95%CI: [0.30, 3.56]). CONCLUSIONS: Late treatment with acetaminophen to avoid surgery for pPDA is associated with reduced ligation but no difference in death/NDI, supporting the safety and effectiveness of this approach.

Cardiac point of care ultrasound in resource limited settings to manage children with congenital and acquired heart disease.

BACKGROUND: In resource limited settings, children with cardiac disease present late, have poor outcomes and access to paediatric cardiology programmes is limited. Cardiac point of care ultrasound was introduced at several Médecins Sans Frontières sites to facilitate cardiopulmonary assessment. We describe the spectrum of disease, case management and outcomes of cases reviewed over the Telemedicine platform. METHODS: Previously ultrasound naïve, remotely placed clinical teams received ultrasound training on focussed image acquisition. The Médecins Sans Frontières Telemedicine platform was utilised for remote case and imaging review to diagnose congenital and acquired heart disease and guide management supported by a remotely situated paediatric cardiologist. RESULTS: Two-hundred thirty-three cases were reviewed between 2016 and 2018. Of 191 who underwent focussed cardiac ultrasound, diagnoses included atrial and ventricular septal defects 11%, atrioventricular septal defects 7%, Tetralogy of Fallot 9%, cardiomyopathy/myocarditis 8%, rheumatic heart disease 8%, isolated pericardiac effusion 6%, complex congenital heart disease 4% and multiple other diagnoses in 15%. In 17%, there was no identifiable abnormality while 15% had inadequate imaging to make a diagnosis. Cardiologist involvement led to management changes in 75% of cases with a diagnosis. Mortality in the entire group was disproportionately higher among neonates (38%, 11/29) and infants (20%, 16/81). There was good agreement on independent review of selected cases between two independent paediatric cardiologists. CONCLUSION: Cardiac point of care ultrasound performed by remote clinical teams facilitated diagnosis and influenced management in cases reviewed over a Telemedicine platform. This is a feasible method to support clinical care in resource limited settings.

Characterization of the Human Coronary Microvascular Response to Multiple Hyperaemic Agents.

BACKGROUND: It is unclear whether the coronary microvascular responses to multiple, mechanistically distinct hyperaemic agents exert similar dilatory responses or share common clinical predictors. This study therefore sought to characterize the index of microvascular resistance (IMR) response to multiple hyperaemic agents in the human coronary circulation. METHODS: Thermodilution-derived IMR was determined during intravenous adenosine, intracoronary acetylcholine, and intravenous dobutamine in patients with ischemic symptoms and nonobstructive coronary angiograms. A total of 128 patients were studied (44 with adenosine and acetylcholine, and 84 with all agents). Adenosine IMR >25, acetylcholine IMR >31, and dobutamine IMR >29 were used to define elevated responses. RESULTS: IMR responses demonstrated weak-to-moderate association (adenosine vs acetylcholine IMR: ρ = 0.33; adenosine vs dobutamine IMR: ρ = 0.51; acetylcholine vs dobutamine IMR: ρ = 0.28; all P < 0.01). Logistic regression analyses revealed that: (1) elevated adenosine IMR was associated with increasing age and left ventricle hypertrophy (odds ratio [OR] = 1.27 and 1.58; both P < 0.05, respectively), (2) elevated acetylcholine IMR was associated with increasing plasma uric acid (OR = 1.09; P < 0.05), and (3) elevated dobutamine IMR was associated with hypertension and left atrial volume index (OR = 3.99 and 1.07; both P < 0.05, respectively). Subset analyses to evaluate clinical utility of the acetylcholine and dobutamine IMR, independent of abnormal adenosine IMR, revealed that elevated acetylcholine and/or dobutamine IMR were associated with higher risk exercise stress tests, left atrial volumes, and burden of exertional chest pain. CONCLUSIONS: Microvascular-specific IMR responses to different hyperaemic agents are only moderately associated, whereas the predictors for agent-specific IMR responses varied, suggesting that multiple pharmacologic agents interrogate different microvascular control mechanisms.

CONTEXTE: On ne sait pas vraiment si les réponses microvasculaires coronariennes à de multiples agents hyperémiques aux modes d'action distincts ont des effets vasodilatateurs similaires ou partagent des facteurs prédictifs cliniques communs. Cette étude visait donc à caractériser la réponse selon l'indice de résistance microvasculaire (IMR) aux multiples agents hyperémiques dans la circulation coronarienne chez l'humain. MÉHODOLOGIE: L'IMR obtenu par thermodilution a été déterminé pendant l'administration intraveineuse d'adénosine, intracoronarienne d'acétylcholine et intraveineuse de dobutamine chez des patients présentant des symptômes ischémiques et par angiogrammes coronariens non obstructifs. Un total de 128 patients (44 avec l'adénosine et l'acétylcholine, et 84 avec tous les agents) ont fait partie de l'étude. Des réponses élevées étaient définies par un IMR à l'adénosine > 25, un IMR à l'acétylcholine > 31 et un IMR à la dobutamine > 29. RÉSULTATS: Les réponses selon l'IMR ont révélé une association faible à modérée (IMR à l'adénosine vs IMR à l'acétylcholine : ρ = 0,33; IMR à l'adénosine vs IMR à la dobutamine : ρ = 0,51; IMR à l'acétylcholine vs IMR à la dobutamine : ρ = 0,28; tous : p < 0,01). Des analyses de régression logistique ont révélé que : 1) un IMR à l'adénosine élevé était associé à l'avancement en âge et à une hypertrophie ventriculaire gauche (rapport des cotes [RC] = 1,27 et 1,58; p < 0,05 respectivement pour les deux), 2) un IMR à l'acétylcholine élevé était associé à l'augmentation de la concentration plasmatique d'acide urique (RC = 1,09; p < 0,05) et 3) un IMR à la dobutamine élevé était associé à l'hypertension et à l'indice de volume auriculaire gauche (RC = 3,99 et 1,07; p < 0,05 respectivement pour les deux). Des analyses par sous-groupes visant à évaluer l'utilité clinique de l'IMR à l'acétylcholine et à la dobutamine, indépendamment d'un IMR à l'adénosine anormal, ont révélé que des IMR à l'acétylcholine et/ou à la dobutamine élevés étaient associés à une augmentation du risque lors des épreuves à l'effort, à un volume auriculaire gauche plus élevé et à une augmentation du fardeau associé à la douleur thoracique à l'effort. CONCLUSIONS: Les réponses microvasculaires selon l'IMR à différents agents hyperémiques sont seulement modérément associées, alors que les facteurs prédictifs des réponses selon l'IMR spécifique de l'agent varient, ce qui laisse croire que les multiples agents pharmacologiques font appel à différents mécanismes de contrôle microvasculaire.

Heterozygous NOTCH1 deletion associated with variable congenital heart defects.

Pathogenic heterozygous variants in the NOTCH1 gene are known to be associated with both left and right-sided congenital cardiac anomalies with strikingly incomplete penetrance and variable phenotypic expressivity. De novo NOTCH1 whole gene deletion has been reported rarely in the literature and its association with cardiac defects is less well established. Here, we report four cases of NOTCH1 gene deletion from two families associated with a spectrum of congenital heart defects from bicuspid aortic valve to complex cardiac anomalies. This is the first description of a familial NOTCH1 deletion, showing apparently high penetrance, which may be unique to this mechanism of disease. Immunohistochemical staining of cardiac tissue demonstrated reduced levels of NOTCH1 expression in both the left and right ventricular outflow tracts. These cases suggest that haploinsufficiency caused by NOTCH1 gene deletion is associated with both mild and severe cardiac defects, similar to those caused by pathogenic variants in the gene, but with apparently higher, if not complete, penetrance.

Intraoperative echocardiographic coronary artery imaging in congenital and acquired heart disease.

Transoesophageal and epicardial echocardiography are indispensible intraoperative imaging modalities to guide paediatric heart disease surgeries and influence surgical decision-making. A less well-described role of intraoperative imaging is its utility in evaluating coronary artery patency and flow. Focused two-dimensional, colour, and spectral Doppler imaging of the coronary arteries should be performed during surgeries involving coronary manipulation or re-implantation, or in cases where there is unexpected ventricular dysfunction or electrographic signs concerning for ischaemia. Intraoperative imaging allows for any anatomical issues to be detected and addressed promptly in the operating room. Imaging of the coronary arteries should identify unobstructed coronary ostia and proximal course without kinking, angulation, narrowing, or significant calibre change to suggest stenosis or extrinsic compression from neighbouring structures. The aim of this review is to highlight the usefulness of transoesophageal and epicardial echocardiography in evaluating coronary artery patency and flow, provide a how-to guide for optimal imaging, and to introduce a practical guideline to achieve best clinical practice.

Improving Prenatal Diagnosis of Coarctation of the Aorta.

BACKGROUND: The purpose of the study was to evaluate the association between fetal echocardiographic measurements and the need for intervention (primary coarctation repair, staged coarctation repair, or catheter intervention) in prenatally diagnosed coarctation of the aorta. METHODS: A single-centre retrospective cohort study (2005-2015) of 107 fetuses diagnosed with suspected coarctation of the aorta in the setting of an apex-forming left ventricle and antegrade flow across the mitral and aortic valves. RESULTS: Median gestational age at diagnosis was 32 weeks (interquartile range, 23-35 weeks). Fifty-six (52%) did not require any neonatal intervention, 51 patients (48%) underwent a biventricular repair. In univariable analysis, an increase in ascending aorta (AAo) peak Doppler flow velocity (odds ratio [OR], 1.40 [95% confidence interval [CI], 1.05-1.91] per 20 cm/s; P = 0.03) was associated with intervention. No intervention was associated with larger isthmus size (OR, 0.23; P < 0.001), transverse arch diameter (OR, 0.23; P < 0.001), and aortic (OR, 0.72; P = 0.02), mitral (OR, 0.58; P = 0.001), and AAo (OR, 0.53; P < 0.001) z-scores. In multivariable analysis, higher peak AAo Doppler (OR, 2.51 [95% CI, 1.54-4.58] per 20 cm/s; P = 0.001) and younger gestational age at diagnosis (OR, 0.81 [95% CI, 0.70-0.93] per week; P = 0.005) were associated with intervention, whereas a higher AAo z-score (OR, 0.65 [95% CI, 0.43-0.94] per z; P = 0.029) and transverse arch dimension (OR, 0.44 [95% CI, 0.18-0.97]; P = 0.05) decreased the risk of intervention. CONCLUSIONS: In prenatally suspected coarctation, the variables associated with intervention comprised smaller AAo and transverse arch size, earlier gestational age at diagnosis, and the additional finding of a higher peak AAo Doppler.

Late oral acetaminophen versus immediate surgical ligation in preterm infants with persistent large patent ductus arteriosus.

OBJECTIVE: The study objective was to evaluate the association of oral acetaminophen therapy versus immediate surgical ligation with neonatal outcomes in infants with persistent patent ductus arteriosus. METHODS: We performed a retrospective cohort study of preterm infants born 28+6 weeks or less gestational age with persistent large patent ductus arteriosus being considered for surgical ligation after unsuccessful medical therapy. Infants in epoch 1 (July 2009 to June 2012) were immediately referred for ligation, and infants in epoch 2 (July 2012 to June 2015) were treated with oral acetaminophen and referred for ligation in the absence of improvement. The primary outcome was a composite of death or chronic lung disease. RESULTS: A total of 92 infants with median (interquartile range) gestational age 25.2 weeks (24.4-26.3) had persistent large patent ductus arteriosus (43 in epoch 1, 49 in epoch 2). Infants in epoch 2 had decreased surgical ligation (26 [53%] vs 31 [72%]; adjusted odds ratio [aOR], 0.32; 95% confidence interval [CI], 0.12-0.89) but increased chronic lung disease (36 [73%] vs 25 [58%]; aOR, 3.34; 95% CI, 1.05-10.58) and increased death/chronic lung disease of borderline significance (39 [80%] vs 29 [67%]; aOR, 3.09; 95% CI, 0.99-9.63). Infants in epoch 2 took longer to wean off of positive pressure ventilation (28.5 vs 24 days after enrollment; aOR, 0.52; 95% CI, 0.31-0.85). CONCLUSIONS: Late oral acetaminophen therapy for infants with persistent patent ductus arteriosus is associated with reduced surgical ligation but increased chronic lung disease. In light of a lack of improvement in clinical outcomes, the individual contributory effects of acetaminophen, surgical ligation, and prolonged exposure to patent ductus arteriosus require further study to define the optimal approach.

Coronary artery Doppler patterns are associated with clinical outcomes post-arterial switch operation for transposition of the great arteries.

Aims: Transposition of the great arteries (TGA) is generally repaired using the arterial switch operation (ASO) involving coronary transfer. The objective of this prospective study was to determine whether specific coronary Doppler patterns intra-operatively predicted adverse early myocardial events. Methods and results: Patients < 3 months old with TGA undergoing the ASO were eligible. All patients (when feasible) underwent an intra-operative transoesophageal echo (TEE) plus an epicardial echo and had pre-op, early post-op, pre-discharge and follow-up functional echocardiograms. The primary endpoint was a composite myocardial ischaemic event (any of: post-operative ST changes, ventricular tachycardia, need for extracorporeal membrane oxygenation (ECMO). Associations of coronary Doppler flow patterns with outcomes were modelled with logistic regression models. From May 2009 to December 2012, 40 patients (29 male, birth weight 3.29 ± 0.58 kg) were recruited. n = 32 had TEE + epicardial, four TEE only, four epicardial only. Seven (18%) patients had an adverse myocardial event (five ST changes, two ventricular tachycardia (one also ECMO). There was one death. n = 3 had a coronary artery (CA) revision post-operatively, and three had re-operation for non-CA causes. By TEE, flow reversal in the left coronary artery was associated with the composite endpoint [Odds Ratio (OR) 31.5, P = 0.004], and for chest open > 3 days (OR 6.67, P = 0.0537). Coronary Doppler flow patterns were similar by TEE and epicardial echo. The tissue Doppler parameters showed an early post-op decrease (P < 0.001 for all measures), with full recovery at follow-up in 31/37 cases. Conclusion: Intra-operative evaluation of coronary artery flow patterns should be considered for patients undergoing the ASO.

Does prenatal diagnosis of hypoplastic left heart syndrome make a difference? - A systematic review.

OBJECTIVE: Hypoplastic left heart syndrome is frequently diagnosed prenatally with variable benefit. We performed a systematic review to evaluate the impact of fetal diagnosis; the primary objective was to evaluate impact on mortality. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Seven databases were searched. Meta-analysis was performed using a random effects model to evaluate the effect of fetal diagnosis on mortality. RESULTS: Literature search revealed 2124 titles and abstracts for screening; 21 full texts were reviewed. Six studies and one abstract were included. Preoperative mortality in 609 neonates (228 prenatal and 381 postnatal) was evaluated. There were 11 deaths in prenatally diagnosed neonates versus 16 deaths in postnatally diagnosed neonates (OR 0.67, 95% CI 0.22-2.01, p = 0.48). Neonates with fetal diagnosis had less preoperative acidosis (mean difference 0.07, 95% CI 0.05, 0.1, p < 0.01) and required less inotropic support (OR 0.16, 95% CI 0.04, 0.7, p = 0.01). Post Stage I, there were 47 deaths in 227 prenatally diagnosed neonates versus 78 deaths in 299 postnatally diagnosed neonates (OR 0.84, 95% CI 0.43, 1.62, p = 0.59). CONCLUSIONS: There is no significant impact of prenatal diagnosis of hypoplastic left heart syndrome on preoperative or post Stage I mortality. Neonates with prenatal diagnosis were hemodynamically more stable. © 2016 John Wiley & Sons, Ltd.