Pre-intervention myocardial stress is a good predictor of aortic valvoluplasty outcome for fetal critical aortic stenosis and evolving HLHS.

Fetal critical aortic stenosis with evolving hypoplastic left heart syndrome (CAS-eHLHS) causes biomechanical and functional aberrations, leading to a high risk of progression to hypoplastic left heart syndrome (HLHS) at birth. Fetal aortic valvuloplasty (FAV) can resolve outflow obstruction and may reduce progression risk. However, it is currently difficult to accurately predict which patients will respond to the intervention and become functionally biventricular (BV) at birth, as opposed to becoming functionally univentricular (UV). This prediction is important for patient selection, parental counselling, and surgical planning. Therefore, we investigated whether biomechanics parameters from pre-FAV image-based computations could robustly distinguish between CAS-eHLHS cases with BV or UV outcomes in a retrospective cohort. To do so we performed image-based finite element biomechanics modelling of nine CAS-eHLHS cases undergoing intervention and six healthy fetal control hearts, and found that a biomechanical parameter, peak systolic myofibre stress, showed a uniquely large difference between BV and UV cases, which had a larger magnitude effect than echocardiography parameters. A simplified equation was derived for quick and easy estimation of myofibre stress from echo measurements via principal component analysis. When tested on a retrospective cohort of 37 CAS-eHLHS cases, the parameter outperformed other parameters in predicting UV versus BV outcomes, and thus has a high potential of improving outcome predictions, if incorporated into patient selection procedures. Physiologically, high myocardial stresses likely indicate a healthier myocardium that can withstand high stresses and resist pathological remodelling, which can explain why it is a good predictor of BV outcomes. KEY POINTS: Predicting the morphological birth outcomes (univentricular versus biventricular) of fetal aortic valvuloplasty for fetal aortic stenosis with evolving HLHS is important for accurate patient selection, parental counselling and management decisions. Computational simulations show that a biomechanics parameter, pre-intervention peak systolic myofibre stress, is uniquely robust in distinguishing between such outcomes, outperforming all echo parameters. An empirical equation was developed to quickly compute peak systolic myofibre stress from routine echo measurements and was the best predictor of outcomes among a wide range of parameters tested.

Fluid Mechanics of Fetal Left Ventricle During Aortic Stenosis with Evolving Hypoplastic Left Heart Syndrome.

In cases of fetal aortic stenosis and evolving Hypoplastic Left Heart Syndrome (feHLHS), aortic stenosis is associated with specific abnormalities such as retrograde or bidirectional systolic transverse arch flow. Many cases progressed to hypoplastic left heart syndrome (HLHS) malformation at birth, but fetal aortic valvuloplasty can prevent the progression in many cases. Since both disease and intervention involve drastic changes to the biomechanical environment, in-vivo biomechanics likely play a role in inducing and preventing disease progression. However, the fluid mechanics of feHLHS is not well-characterized. Here, we conduct patient-specific echocardiography-based flow simulations of normal and feHLHS left ventricles (LV), to understand the essential fluid dynamics distinction between the two cohorts. We found high variability across feHLHS cases, but also the following unifying features. Firstly, feHLHS diastole mitral inflow was in the form of a narrowed and fast jet that impinged onto the apical region, rather than a wide and gentle inflow in normal LVs. This was likely due to a malformed mitral valve with impaired opening dynamics. This altered inflow caused elevated vorticity dynamics and wall shear stresses (WSS) and reduced oscillatory shear index at the apical zone rather than mid-ventricle. Secondly, feHLHS LV also featured elevated systolic and diastolic energy losses, intraventricular pressure gradients, and vortex formation numbers, suggesting energy inefficiency of flow and additional burden on the LV. Thirdly, feHLHS LV had poor blood turnover, suggesting a hypoxic environment, which could be associated with endocardial fibroelastosis that is often observed in these patients.

Fetal aortic valvuloplasty: first report of two cases from Saudi Arabia.

BACKGROUND: Fetal aortic stenosis may progress to hypoplastic left heart syndrome (HLHS), which carries a poor prognosis. We report two infants with fetal aortic stenosis successfully treated with fetal aortic valvuloplasty (FAV) using balloon dilatation. CASE PRESENTATION: Of five fetuses with aortic stenosis fulfilling the FAV criteria of severe aortic stenosis with a left ventricular length Z-score of ≥ - 2, retrograde flow in the transverse aortic arch, left-to-right flow across the foramen ovale, monophasic mitral inflow, and significant left ventricular dysfunction, we obtained permission for FAV in two fetuses. FAV was performed successfully under echocardiographic guidance using balloon dilatation. Both fetuses survived to birth. During FAV, mild pericardial effusion developed when introducing the stylet needle in the second fetus, and this resolved within 48 h. No intraprocedural complications occurred in the first patient, and no maternal complications occurred. The first infant underwent the Ross procedure after birth and is currently 7 years old and doing well. The second patient underwent aortic and mitral valve repair with endocardial fibroelastosis resection approximately 2 weeks after birth, which temporarily addressed the mitral valve stenosis; high doses of inotropes were subsequently required. The infant died of sepsis at 2 months of age. CONCLUSION: FAV using balloon dilatation to treat fetal aortic stenosis was successful in our two patients, with subsequent neonatal biventricular repair resulting in long-term survival in one patient and death secondary to sepsis in the second patient.

Induction of left ventricular hypoplasia by occluding the foramen ovale in the fetal lamb.

Disturbed fetal haemodynamics often affects cardiac development and leads to congenital cardiac defects. Reduced left ventricular (LV) preload in the fetus may result in hypoplastic LV, mitral and aortic valve, mimicking a moderate form of hypoplastic left heart complex. We aimed to induce LV hypoplasia by occluding the foramen ovale (FO) to reduce LV preload in the fetal sheep heart, using percutaneous trans-hepatic catheterisation. Under maternal anaesthesia and ultrasound guidance, hepatic venous puncture was performed in six fetal lambs (0.7-0.75 gestation). A coronary guidewire was advanced into the fetal inferior vena cava, right and left atrium. A self-expandable stent was positioned across the FO. An Amplatzer Duct Occluder was anchored within the stent for FO occlusion. Euthanasia and post-mortem examination was performed after 3 weeks. Nine fetuses were used as age-matched controls. Morphometric measurements and cardiac histopathology were performed. Compared with controls, fetal hearts with occluded FO had smaller LV chamber, smaller mitral and aortic valves, lower LV-to-RV ratio in ventricular weight and wall volume, and lower number of LV cardiomyocyte nuclei. We conclude that fetal FO occlusion leads to a phenotype simulating LV hypoplasia. This large animal model may be useful for understanding and devising therapies for LV hypoplasia.

Fetal cardiac intervention-Perspectives from a single center.

Fetal cardiac intervention was first proposed in the early 1990s to impact cardiac development and survival of fetuses with fetal aortic stenosis and evolving hypoplastic left heart syndrome (HLHS). Although initial attempts of fetal aortic valvuloplasty were unsuccessful and carried a high rate of morbidity and mortality, our collaborative group at the Brigham and Women's Hospital and Boston Children's Hospital have reinvigorated the procedure using improvements in imaging, anesthesia, balloon catheters, and surgical techniques. Two decades of experience have now allowed us to document the safety of in utero intervention and to achieve a better understanding of the impact of midgestation intervention on developing HLHS. Research into underlying genetics, predictive biomarkers, and ways to incorporate stem cell technology will hopefully allow us to further refine the procedure to most benefit children with this historically lethal disease.

Endocardial Fibroelastosis is Secondary to Hemodynamic Alterations in the Chick Embryonic Model of Hypoplastic Left Heart Syndrome.

BACKGROUND: Endocardial fibroelastosis (EFE) is a diffuse thickening of the ventricular endocardium, causing myocardial dysfunction and presenting as unexplained heart failure in infants and children. One of the postulated causes is persistent and increased wall tension in the ventricles. RESULTS: To examine whether reduced ventricular pressure in a chick model of hypoplastic left heart syndrome (HLHS) induced by left atrial ligation (LAL) at embryonic day (ED) 4 is associated with EFE at later stages, myocardial fibrosis was evaluated by histology and immunoconfocal microscopy and mass spectrometry (MS) at ED12. Immunohistochemistry with collagen I antibody clearly showed a significant thickening of the layer of subendocardial fibrous tissue in LAL hearts, and MS proved this significant increase of collagen I. To provide further insight into pathogenesis of this increased fibroproduction, hypoxyprobe staining revealed an increased extent of hypoxic regions, normally limited to the interventricular septum, in the ventricular myocardium of LAL hearts at ED8. CONCLUSIONS: Abnormal hemodynamic loading during heart development leads to myocardial hypoxia, stimulating collagen production in the subendocardium. Therefore, EFE in this chick embryonic model of HLHS appears to be a secondary effect of abnormal hemodynamics. Developmental Dynamics 247:509-520, 2018. © 2017 Wiley Periodicals, Inc.

Development and maturation of the fibrous components of the arterial roots in the mouse heart.

The arterial roots are important transitional regions of the heart, connecting the intrapericardial components of the aortic and pulmonary trunks with their ventricular outlets. They house the arterial (semilunar) valves and, in the case of the aorta, are the points of coronary arterial attachment. Moreover, because of the semilunar attachments of the valve leaflets, the arterial roots span the anatomic ventriculo-arterial junction. By virtue of this arrangement, the interleaflet triangles, despite being fibrous, are found on the ventricular aspect of the root and located within the left ventricular cavity. Malformations and diseases of the aortic root are common and serious. Despite the mouse being the animal model of choice for studying cardiac development, few studies have examined the structure of their arterial roots. As a consequence, our understanding of their formation and maturation is incomplete. We set out to clarify the anatomical and histological features of the mouse arterial roots, particularly focusing on their walls and the points of attachment of the valve leaflets. We then sought to determine the embryonic lineage relationships between these tissues, as a forerunner to understanding how they form and mature over time. Using histological stains and immunohistochemistry, we show that the walls of the mouse arterial roots show a gradual transition, with smooth muscle cells (SMC) forming the bulk of wall at the most distal points of attachments of the valve leaflets, while being entirely fibrous at their base. Although the interleaflet triangles lie within the ventricular chambers, we show that they are histologically indistinguishable from the arterial sinus walls until the end of gestation. Differences become apparent after birth, and are only completed by postnatal day 21. Using Cre-lox-based lineage tracing technology to label progenitor populations, we show that the SMC and fibrous tissue within the walls of the mature arterial roots share a common origin from the second heart field (SHF) and exclude trans-differentiation of myocardium as a source for the interleaflet triangle fibrous tissues. Moreover, we show that the attachment points of the leaflets to the walls, like the leaflets themselves, are derived from the outflow cushions, having contributions from both SHF-derived endothelial cells and neural crest cells. Our data thus show that the arterial roots in the mouse heart are similar to the features described in the human heart. They provide a framework for understanding complex lesions and diseases affecting the aortic root.

Intermediate term thrombotic risk in contemporary total cavo-pulmonary connection for single ventricle circulations.

Despite the common occurrence of thrombosis in Fontan circulations, the mid-term thrombotic risk beyond the first two postoperative years is poorly defined especially in total cavo pulmonary Fontan. This study examines the thrombotic incidence and risk beyond the first 2 years after contemporary Fontan surgery. Using a retrospective cohort study design, 89 Fontan patients, 50 male, were included and evaluated with a median of 8.3 years (IQR 6.8-11.4) follow-up. Hospital records were reviewed for known risk factors of thrombosis, thrombotic events, antiplatelet and anticoagulation management, and basic characteristics. Forty seven patients (52%) had a dominant left ventricle, and 28 (32%) had hypoplastic left heart syndrome. Eight patients had thrombotic events post Fontan surgery at a median age of 9 years (IQR 5.6-13), 5.7 (IQR 2.0-9.7) years following surgery, not including events that occurred immediately peri-operatively. Four thrombotic events were intracardiac whereas the remainder were extra-cardiac. There was no significant univariate correlation between thrombosis and the presence of ventricular morphology, pulmonary arterial reconstruction, or type of cavopulmonary anastomosis (lateral tunnel vs. extracardiac conduit). Thrombosis continues to be an important intermediate-term risk even for patients with contemporary Fontan circulations. These results strongly suggest that thrombophilic risk is not dictated purely by vascular pathway and hemodynamic variables. Further investigation into the pathophysiology, individualized risk, and effectiveness of anticoagulation strategies are required in this high risk population.

Proportion of selected congenital heart defects attributable to recognized risk factors.

PURPOSE: To assess the contribution of multiple risk factors for two congenital heart defects-hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot (TOF). METHODS: We used data from the National Birth Defects Prevention Study (1997-2011) to estimate average adjusted population attributable fractions for several recognized risk factors, including maternal prepregnancy overweight-obesity, pregestational diabetes, age, and infant sex. RESULTS: There were 594 cases of isolated simple HLHS, 971 cases of isolated simple TOF, and 11,829 controls in the analysis. Overall, 57.0% of HLHS cases and 37.0% of TOF cases were estimated to be attributable to risk factors included in our model. Among modifiable HLHS risk factors, maternal prepregnancy overweight-obesity accounted for the largest proportion of cases (6.5%). Among modifiable TOF risk factors, maternal prepregnancy overweight-obesity and maternal age of 35 years or older accounted for the largest proportions of cases (8.3% and 4.3%, respectively). CONCLUSIONS: Approximately half of HLHS cases and one-third of TOF cases were estimated to be attributable to risk factors included in our models. Interventions targeting factors that can be modified may help reduce the risk of HLHS and TOF development. Additional research into the etiology of HLHS and TOF may reveal other modifiable risk factors that might contribute to primary prevention efforts.

The myocardial and coronary histopathology and pathogenesis of hypoplastic left heart syndrome.

Hypoplastic left heart syndrome has the greatest mortality rate among all CHDs and without palliation is uniformly fatal. Despite noble efforts, the aetiology of this syndrome is unknown and a cure remains elusive. The genetic and anatomic heterogeneity of hypoplastic left heart syndrome supports a rethinking of old hypotheses and warrants further investigation into the histological and vascular variations recognised with this syndrome. In an effort to elucidate the pathogenesis of hypoplastic left heart syndrome, this review will focus on its unique myocardial and coronary pathology as well as evaluate the association of hypoplastic left heart syndrome with the endocardial fibroelastosis reaction.

Restrictive atrial septum after the Fontan procedure.

In this study, three patients presenting with early or late postoperative Fontan complications were identified to suffer from restriction of the native atrial septum. This caused significant obstruction to pulmonary venous return and elevated systemic venous pressure. Dobutamine stress testing was used in one patient to identify this lesion. Transcatheter stenting was performed in the other two patients. Patients improved after relief of the obstruction.

Fetal aortic valve stenosis: a critique of case selection criteria for fetal intervention.

OBJECTIVE: Selection of fetuses with aortic stenosis (AS) for prenatal intervention has been influenced by published scoring systems. This study aimed to test these scoring systems by retrospective application to consecutive cases of fetal AS. METHODS: Retrospective analysis of the echocardiographic findings of 31 consecutive fetuses with AS evaluated at a tertiary fetal cardiology centre. Published 'eHLHS' scores and threshold scores were applied to the group and compared to postnatal management, in terms of biventricular repair versus single ventricle palliation. RESULTS: Thirty-one fetuses were identified with AS, and eHLHS was identified in 17 at the initial echocardiogram. No fetus with a full eHLHS score (3/3 or 4/4) achieved a biventricular repair. Three fetuses had a favourable threshold score (≥4), one of whom had a successful biventricular outcome. Seven fetuses had an unfavourable threshold score (<4) and underwent a univentricular pathway. CONCLUSION: The eHLHS score is a reliable predictor for the progression to HLHS at term. The score identifies those who would achieve a biventricular repair postnatally without prenatal intervention. A minority of fetuses with favourable threshold scores may achieve a biventricular repair postnatally without prenatal intervention, but eHLHS and an unfavourable threshold score (<4) predict a single ventricle pathway postnatally.

Foetal aortic valvuloplasty: experience of five cases.

OBJECTIVES: Foetal aortic valvuloplasty has been proposed as a strategy to improve left heart growth and function in foetuses with severe aortic stenosis at risk of progression to hypoplastic left heart syndrome. We report our experience with this intervention. METHODS AND RESULTS: Between 2005 and 2010, five foetuses with aortic stenosis and at risk of progression to hypoplastic left heart syndrome underwent ultrasound-guided percutaneous foetal aortic valvuloplasty. There were no associated maternal complications or foetal demise. In one case, the pregnancy was terminated a couple of weeks after the intervention, one foetus evolved to hypoplastic left heart syndrome, and three did not. CONCLUSIONS: Foetal aortic valvuloplasty seems to be a safe and feasible procedure. It has been reported that it has the potential to prevent progression to hypoplastic left heart syndrome in selected foetuses with severe aortic stenosis. Further investigation regarding physiological and clinical aspects of this disease both prenatally and postnatally will probably allow to improve therapeutic strategies and clinical outcome.

Aortic dilatation and aortopathy in congenital heart diseases.

Longer survival after corrective surgery for congenital heart diseases has rendered late complications more important. One of these complications is aortic dilatation which may occur in patients with repaired or unrepaired disease and can progress to aneurysm, dissection, and rupture. This aortic dilatation in various congenital heart diseases does not simply mean anatomical dilatation of the aortic root, but it closely relates to the aortic pathophysiological abnormality, aortic regurgitation, and aortic and ventricular dysfunction; therefore, we can recognize this complex lesion as a new concept: "aortopathy". The pathophysiology of this disease is complex and only partially understood. In this review, we first discuss history, pathophysiology, and clinical features of aortic dilatation and aortopathy of congenital heart disease. Then we provide a review of the evaluation and management of this disease.

The risk for four specific congenital heart defects associated with assisted reproductive techniques: a population-based evaluation.

STUDY QUESTION: Are the risks of hypoplastic left heart syndrome, transposition of great arteries, tetralogy of Fallot (TOF) and coarctation of the aorta increased in infants conceived by different assisted reproductive techniques (ARTs)? STUDY ANSWER: ARTs, and particularly intracytoplasmic sperm injection (ICSI), are specifically associated with a higher risk of TOF. WHAT IS ALREADY KNOWN: ARTs are associated with an increase in the overall risk of birth defects. The risk for congenital heart defects (CHDs) associated with ARTs has been evaluated as a whole but there is limited information on the risks for specific CHDs. STUDY DESIGN, MATERIAL AND METHODS: We conducted a case-control study using population-based data from the Paris registry of congenital malformations for the period 1987-2009 and a cohort study of CHD (EPICARD) on 1583 cases of CHDs and 4104 malformed controls with no known associations with ARTs. ARTs included ovulation induction only, IVF and ICSI. RESULTS: Exposure to ARTs was significantly higher for TOF than controls (6.6 versus 3.5%, P = 0.002); this was not the case for the other three CHDs. ARTs (all methods combined) were associated with a 2.4-fold higher odds of TOF after adjustment for maternal characteristics, paternal age and year of birth [adjusted odds ratios (OR): 2.4, 95% confidence interval (CI): 1.5-3.7] with the highest risk associated with ICSI (adjusted OR: 3.0, 95% CI: 1.0-8.9). No statistically significant associations were found for the other CHDs. LIMITATIONS: Our study cannot disentangle to what extent the observed associations between the risk of TOF and ARTs are due to causal effects of ARTs and/or the underlying infertility problems of couples who conceive following ART. IMPLICATIONS: The developmental basis of the specific association between the risk of TOF and ARTs need to be further investigated.

Hypoplastic left heart syndrome and other left heart disease: evolution of understanding from population-based analysis to molecular biology and back again--a brief overview.

Congenital cardiac disease is the most common birth defect, occurring in approximately 1 in 1000 live births. Congenital cardiac defects have associations, whether with gender, race, or specific chromosomal abnormalities, potentially allowing grouping of defects to be studied in an effort to develop an understanding of aetiological factors. The Baltimore-Washington Infant Study provides full ascertainment of a population of infants with congenital cardiac disease born in a defined geographic region. The fundamental hypotheses generated at the inception of the Baltimore-Washington Infant Study included the central idea that the outcome of birth, including the development of congenital cardiac malformations, was influenced by environmental factors and their route of introduction into a genetically susceptible host. Evidence exists that supports the concept that both genetic and environmental factors contribute to the development of diseases of the left heart.

Use of a pressure guidewire in fetal cardiac intervention for critical aortic stenosis.

Fetal cardiac intervention for critical aortic stenosis (AS) with evolving hypoplastic left heart syndrome is performed in an attempt to maintain a biventricular circulation postnatally. The procedure has been hindered by technical challenges and poor candidate selection. We report here the novel use of a pressure guidewire during aortic valvuloplasty in a fetus at 21 weeks' gestation with critical AS and evolving hypoplastic left heart syndrome. Use of a pressure guidewire during fetal cardiac intervention offers several potential advantages over existing protocols. This technique augments fetal ultrasound as it relates to operator awareness of catheter and wire position (with continuous monitoring of pressure waveforms), improves on intraprocedural fetal hemodynamic monitoring and responsiveness to resuscitation, and provides a rich new data set of invasive fetal hemodynamics. This data set offers tremendous potential with regards to improving candidate selection and postintervention prognostication. In addition, we provide the first, to our knowledge, characterization of intracardiac pressures in a human fetus with congenital heart disease. Given the realized and potential benefits associated with this technique, use of a pressure guidewire may become standard of care for all fetal cardiac interventions.

Persistent left superior vena cava: does it have a role in the pathogenesis of hypoplastic left heart syndrome?

The coexistence of a persistent left superior vena cava (PLSVC) and congenital anomalies, both cardiac and noncardiac, is well documented, but whether PLSVC contributes to the development of cardiac malformations is controversial. We conducted a retrospective review of perinatal and pediatric autopsies to determine the association between PLSVC and other congenital anomalies. Of 362 patients, 91 (25%) had congenital heart disease and 19 (5.2%) had PLSVC. Eight cases (47%) were associated with specific syndromes, including heterotaxy syndrome, trisomy 18, trisomy 13, and Jacobsen syndrome. Seventeen cases of PLSVC (89%) were associated with congenital heart disease, most of which were complex. Isolated PLSVC was found in 2 cases (11%). Eight of the 19 PLSVC cases (47%) were associated with hypoplastic left heart syndrome (HLHS), a result that was statistically significant (P  =  0.041). Left ventricle inflow/outflow obstruction is believed to be a critical pathogenic factor in the development of HLHS. Whereas 5 of 8 cases of HLHS had additional obstructive cardiac outflow tract lesions, 3 of 8 cases did not. PLSVC is known to be able to compromise left ventricle inflow via a dilated coronary sinus, and we speculate that PLSVC may have played a contributing role in the pathogenesis of HLHS in these three cases. As an isolated lesion, PLSVC would not be sufficient to cause HLHS, but it might contribute in combination with other obstructive lesions, or in the setting of other genetic and/or environmental factors still to be defined for HLHS. A larger series will be needed to confirm this hypothesis.

Severe left ventricular hypoplasia in patients with unbalanced incomplete atrioventricular septal defect and pulmonary hypertension: feasibility of biventricular repair.

We report three patients with partial atrioventricular septal defect who presented in the neonatal period with excessive left to right shunting and progressive pulmonary hypertension. Successful biventricular repair was accomplished despite the fact that left ventricular area and left sided structures did not meet the criteria established previously for biventricular management in children with critical aortic stenosis or complete atrioventricular septal defect. Indication for biventricular management was based on the fact that none of our patients had morphological mitral or aortic stenosis and that the hypoplastic left ventricle proved capable to maintain the systemic circulation following closure of the arterial duct. Fenestrated closure of the atrial septum and an individualized approach regarding the closure of the cleft in the left sided atrioventricular valve appear to be important surgical options to reduce postoperative left atrial pressure and to allow the ventricles to adapt to the new loading conditions.