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.

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.

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.

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.

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.

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.

Comparison of Immune Profiles in Fetal Hearts with Idiopathic Dilated Cardiomyopathy, Maternal Autoimmune-Associated Dilated Cardiomyopathy and the Normal Fetus.

The etiology of idiopathic dilated cardiomyopathy (iDCM) remains unknown. Immune therapies have improved outcome in fetuses with DCM born to mothers with autoimmune disease (aDCM). The purpose of this retrospective study was to compare the myocardial B and T cell profiles in fetuses and neonates with idiopathic DCM (iDCM) versus autoimmune-mediated DCM (aDCM) and to describe the normal cell maturation within the human fetal myocardium. Of 60 fetal autopsy cases identified from institutional databases, 10 had aDCM (18-38 weeks), 12 iDCM (19-37 weeks) and 38 had normal hearts (11-40 weeks). Paraffin-embedded myocardium sections were stained for all lymphocyte (CD45), B cells (CD20, CD79a), T cells (CD3, CD4, CD7, CD8) and monocyte (CD68) surface markers. Two independent, blinded cell counts were performed. Normal hearts expressed all B and T cell markers in a bimodal fashion, with peaks at 22 and 37 weeks of gestation. The aDCM cohort was most distinct from normal hearts, with less overall T cell markers [EST -9.1 (2.6) cells/mm(2), p = 0.001], CD4 [EST -2.0 (0.6), p = 0.001], CD3 [EST -3.9 (1.0), p < 0.001], CD7 [EST -3.0 (1.1), p = 0.01] overall B cell markers [EST -4.9 (1.8), p = 0.01] and CD79a counts [EST -2.3 (0.9), p = 0.01]. The iDCM group had less overall B cell markers [EST -4.0 (1.8), p = 0.03] and CD79a [EST -1.7 (0.9), p = 0.05], but no difference in T cell markers. Autoimmune-mediated DCM fetuses have less B and T cell markers, whereas iDCM fetuses have less B cell markers compared with normal fetal hearts. The fetal immune system may play a role in the normal development of the heart and evolution of dilated cardiomyopathy.

A unique foetal case of left ventricular non-compaction associated with arrhythmia, structural cardiac anomalies, and agenesis of the ductus venosus.

A 21-week gestational age foetus was diagnosed with left ventricular non-compaction, Ebstein's anomaly, sinus bradycardia, first-degree heart block, and agenesis of the ductus venosus. The prognosis was guarded given the constellation of findings, and the foetus was monitored closely. Despite a potentially poor outcome, the foetus survived. Prognosis in foetally diagnosed left ventricular non-compaction is usually poor; however, rarely, foetuses can survive postnatally.

The impact of not having a ductus arteriosus on clinical outcomes in foetuses diagnosed with tetralogy of Fallot.

BACKGROUND: Foetuses with simple tetralogy of Fallot almost universally have a patent ductus arteriosus. Two recently identified cases had an absent patent ductus arteriosus, requiring emergent intervention at birth. The objective of this study was to determine whether foetuses diagnosed with tetralogy of Fallot and no patent ductus arteriosus have poorer outcomes compared with those with tetralogy of Fallot+patent ductus arteriosus. METHODS: All foetal cases of tetralogy of Fallot between January, 2000 and 2012 were retrospectively identified from The Hospital for Sick Children (Toronto, Canada) database. Cases - tetralogy of Fallot+no patent ductus arteriosus confirmed on postnatal echo - and controls - tetralogy of Fallot+patent ductus arteriosus, matched for gestational age - were identified from prenatal records, and both clinical and echocardiographic data were reviewed. Optimal outcome was defined as valve-sparing repair with no residual lesions. Student's t-tests and Fisher's exact χ2 were used to compare groups. RESULTS: n=115 foetuses were diagnosed with tetralogy of Fallot: 11 (9%) had no patent ductus arteriosus, and were matched to 22 controls - mean gestational age at diagnosis 23.2±4.2 weeks, 23.4±6.6 weeks, respectively. Cases had a higher proportion of right aortic arches (64% versus 14%, p<0.001). Foetal and postnatal echocardiographic data did not reveal significant differences in branch pulmonary artery sizes, pulmonary valve sizes, or ventricular function. No differences were identified for cyanosis at birth (2/10 versus 7/20, p=0.67), or catheter intervention (5/10 versus 4/22, p=0.12). Optimal outcome rates were similar between cases and controls (4/11 (36%) versus 5/21 (24%), p=0.68). CONCLUSIONS: The patent ductus arteriosus does not appear to have an impact on clinical outcome in foetuses with tetralogy of Fallot.

Factors associated with in utero demise of fetuses that have underlying cardiac pathologies.

Factors associated with in utero fetal demise (IUFD) of fetuses that have underlying cardiac pathologies are largely unknown. This case-control study aimed to define the prevalence of IUFD in fetuses with a diagnosis of cardiac pathologies and to identify prenatal predictors of IUFD. Between January 2004 and December 2010, 74 IUFD cases [4.6 %; 95 % confidence interval (CI) 3.7-5.8 %] were identified from 1,584 cases with a diagnosis of structural or functional cardiac lesions in the Hospital for Sick Children database. The cases were divided into right-sided (N = 28), left-sided (N = 23), great artery (N = 8), and miscellaneous (N = 15) groups. The control subjects (1:1 ratio) were fetuses that had cardiac pathology diagnosed within 48 h of the IUFD case. Multivariable regression models were used to determine echocardiographic predictors of IUFD. The prevalence of IUFD was greatest in hypertrophic cardiomyopathy (8/16, 50 %) and Ebstein's anomaly/tricuspid dysplasia (4/15, 27 %) and lowest in transposition of the great arteries (2/85, 1 %). The findings showed IUFD to be associated with hydrops in 17 (23 %) of the 74 cases and arrhythmia in 11 (15 %) of the 74 cases. The factors identified by univariable logistic regression analyses were right ventricular dysfunction [odds ratio (OR) 2.7; p = 0.001], left ventricular dysfunction (OR 1.8; p = 0.007), umbilical vein pulsations (OR 10.9; p = 0.002), and abnormal ductus venosus flow (OR 3.3; p = 0.01). The factors associated with IUFD in multivariable logistic regression models were cardiomegaly (OR 5.6; p = 0.01), hydrops (OR 29.5; p = 0.001), pericardial effusion (OR 4.1; p = 0.06), and extracardiac abnormalities (OR 7.2; p < 0.001). The prevalence of IUFD is greatest in conditions affecting the ventricular myocardium. The onset of IUFD appears to be related initially to right ventricular dysfunction. Closer surveillance is recommended for lesions at risk of IUFD.

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.

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.

Foetal echocardiographic assessment of borderline small left ventricles can predict the need for postnatal intervention.

BACKGROUND: We sought to prospectively determine foetal echocardiographic factors associated with neonatal interventions in borderline hypoplastic left ventricles. METHODS: Foetuses were included who had a left ventricle that was 2-4 standard deviations below normal for length or diameter and had forward flow across the mitral and aortic valves. Factors associated with an intervention in the first month of life or no need for intervention were sought using univariate and multivariate logistic regression models. RESULTS: From 2005 to 2008, 47 foetuses meeting the criteria had an additional diagnosis (+foetal coarctation/+transverse arch hypoplasia): atrioventricular septal defect 7 (+2/+0), double outlet right ventricle 2 (+0/+0), Shone's complex 19 (+9/+4), and ventricular disproportion 19 (+13/+11; 4 both). There were seven pregnancies terminated, three foetal demises, and five had compassionate care. There were 32 livebirths that either had a biventricular repair (n = 20, n = 2 dead), univentricular palliation (n = 2, both alive), or no intervention (n = 9). Overall survival of livebirths to 6 months of age was 79%. Factors associated with early intervention on first foetal echocardiogram were: obstructed or retrograde arch flow (p = 0.08, odds ratio 3.3), coarctation (p = 0.05, odds ratio 11.4), and left ventricle outflow obstruction (p = 0.05, odds ratio 12.5). Neonatal factors included: Shone's diagnosis (p = 0.02, odds ratio 4.9), bicuspid aortic valve (p = 0.005, odds ratio 11.7), and larger tricuspid valve z-score (p = 0.05, odds ratio 3.6). A neonatal factor associated with no intervention was a larger mitral valve z-score (mean 23.8 versus 24.2 intervention group, p = 0.04, odds ratio 2.8). DISCUSSION: The need for early intervention in foetuses with borderline hypoplastic left ventricle can be predicted by foetal echocardiography.

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.

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.

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.

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.

The myocardium of fetuses with endocardial fibroelastosis contains fewer B and T lymphocytes than normal control myocardium.

The observation that endocardial fibroelastosis (EFE) can result from an immune response to maternal autoantibody deposition in the fetal myocardium raises the possibility that the fetal immune system may contribute to the pathogenesis of idiopathic EFE and dilated cardiomyopathy (DCM). This study sought to characterize myocardial immune cell presence in fetuses and neonates with idiopathic EFE + DCM, in those with EFE + structural heart disease, and in normal control subjects. Paraffin tissue sections from fetuses identified from the pathology database were stained for B cell, T cell, macrophage, and general hematopoietic cell surface markers. Of the 14 fetuses included in the study, 5 had EFE + DCM, 4 had EFE + structural heart disease, and 5 were normal control fetuses. The EFE + DCM group had fewer B cells than the control group (0.15 vs. 0.44 cells/mm(2); p = 0.005). The EFE + heart disease group had both fewer B cells (0.18 vs. 0.44 cells/mm(2); p = 0.08) and T cells (0.29 vs. 0.80 cells/mm(2); p = 0.04) than the control group. The CD4/CD8 ratio was similar in the EFE + DCM and EFE + heart disease groups (1.0 vs. 0.9; p = 0.17) but higher in the EFE + DCM group than in the control group (0.9 vs. 0.3; p = 0.03). The myocardium of fetuses with EFE contains fewer B and T lymphocytes than normal control fetuses.