Hspb7 is a cardioprotective chaperone facilitating sarcomeric proteostasis.

Small heat shock proteins are chaperones with variable mechanisms of action. The function of cardiac family member Hspb7 is unknown, despite being identified through GWAS as a potential cardiomyopathy risk gene. We discovered that zebrafish hspb7 mutants display mild focal cardiac fibrosis and sarcomeric abnormalities. Significant mortality was observed in adult hspb7 mutants subjected to exercise stress, demonstrating a genetic and environmental interaction that determines disease outcome. We identified large sarcomeric proteins FilaminC and Titin as Hspb7 binding partners in cardiac cells. Damaged FilaminC undergoes autophagic processing to maintain sarcomeric homeostasis. Loss of Hspb7 in zebrafish or human cardiomyocytes stimulated autophagic pathways and expression of the sister gene encoding Hspb5. Inhibiting autophagy caused FilaminC aggregation in HSPB7 mutant human cardiomyocytes and developmental cardiomyopathy in hspb7 mutant zebrafish embryos. These studies highlight the importance of damage-processing networks in cardiomyocytes, and a previously unrecognized role in this context for Hspb7.

Zebrafish model of amyloid light chain cardiotoxicity: regeneration versus degeneration.

Cardiac dysfunction is the most frequent cause of morbidity and mortality in amyloid light chain (AL) amyloidosis caused by a clonal immunoglobulin light chain (LC). Previously published transgenic animal models of AL amyloidosis have not recapitulated the key phenotype of cardiac dysfunction seen in AL amyloidosis, which has limited our understanding of the disease mechanisms in vivo, as well as the development of targeted AL therapeutics. We have developed a transgenic zebrafish model in which a λ LC derived from a patient with AL amyloidosis is conditionally expressed in the liver under the control of the Gal4 upstream activation sequence enhancer system. Circulating LC levels of 125 µg/ml in these transgenic zebrafish are comparable to median pathological serum LC levels. Functional analysis links abnormal contractile function with evidence of cellular and molecular proteotoxicity in the heart, including increased cell death and autophagy. However, despite pathological and functional phenotypes analogous to human AL, the lifespan of the transgenic fish is comparable to control fish without the expressed AL-LC transgene. Nuclear labeling experiments suggest increased cardiac proliferation in the transgenic fish, which can be counteracted by treatment with a small molecule proliferation inhibitor leading to increased zebrafish mortality because of cardiac apoptosis and functional deterioration. This transgenic zebrafish model provides a platform to study underlying AL disease mechanisms in vivo further. NEW & NOTEWORTHY Heart failure is a major cause of mortality in amyloid light (AL) amyloidosis, yet it has been difficult to model in animals. We report the generation of a transgenic zebrafish model for AL amyloidosis with pathological concentration of circulating human light chain protein that results in cardiac dysfunction. The light chain toxicity triggers regeneration in the zebrafish heart resulting in functional compensation early in life, but with age develops into cardiac dysfunction.

Tmem88a mediates GATA-dependent specification of cardiomyocyte progenitors by restricting WNT signaling.

Biphasic control of WNT signaling is essential during cardiogenesis, but how the pathway switches from promoting cardiac mesoderm to restricting cardiomyocyte progenitor fate is unknown. We identified genes expressed in lateral mesoderm that are dysregulated in zebrafish when both gata5 and gata6 are depleted, causing a block to cardiomyocyte specification. This screen identified tmem88a, which is expressed in the early cardiac progenitor field and was previously implicated in WNT modulation by overexpression studies. Depletion of tmem88a results in a profound cardiomyopathy, secondary to impaired cardiomyocyte specification. In tmem88a morphants, activation of the WNT pathway exacerbates the cardiomyocyte deficiency, whereas WNT inhibition rescues progenitor cells and cardiogenesis. We conclude that specification of cardiac fate downstream of gata5/6 involves activation of the tmem88a gene to constrain WNT signaling and expand the number of cardiac progenitors. Tmem88a is a novel component of the regulatory mechanism controlling the second phase of biphasic WNT activity essential for embryonic cardiogenesis.

Is There a Measurable Difference between the Left and Right Modified Myocardial Performance Indices, and Does This Change to Reflect Unilateral Myocardial Dysfunction in Pathology?

INTRODUCTION: Fetal cardiac dysfunction may manifest itself unilaterally as right and left ventricles differing in design, function and load, measurable as differing in myocardial performance indices (MPIs). We wished to define this difference ('delta-MPI' or DMPI), present its normal range and pilot its use in pathological pregnancy. MATERIAL AND METHODS: Prospective cross-sectional study of 324 normal singleton fetuses (16-38 weeks of gestation). Left and right modified MPI (LMPI and RMPI) were performed during a single examination using the 'peak' valve click technique. Thirty-seven pathological singleton and monochorionic diamniotic twin pregnancies were compared as pilot data. RESULTS: Modified MPIs (mean ± SD) were 0.45 ± 0.06 (LMPI) and 0.47 ± 0.09 (RMPI), being similar at 18 weeks' gestation with DMPI increasing slightly throughout pregnancy (0.02 ± 0.08). Both singleton intrauterine growth restriction (IUGR) and recipient twin-twin transfusion syndrome (TTTS) showed significantly elevated RMPI, LMPI and DMPI, most pronounced for DMPI (450 and 500% increase, respectively; p < 0.01). DMPI acquisition rates were 83.3% normal and 87.0% pathological. DISCUSSION: We demonstrate for the first time differing intrafetal LMPI and RMPI in a large gestational cohort, with this difference increasing with gestational age. Pilot data confirm the potential for DMPI as a tool to assess unilateral myocardial function in singleton IUGR and recipient twins in TTTS, and further studies are under way to evaluate its clinical utility.

[Genetic and prenatal diagnosis for a Chinese family with primary carnitine deficiency].

OBJECTIVE: To identify potential mutation of SLC22A5 gene in a 5-month-old boy affected with primary carnitine deficiency and provide genetic counseling and prenatal diagnosis for the members of his family. METHODS: DNA was extracted from peripheral blood samples derived from the proband, his parents and elder sister, as well as amniotic fluid from his pregnant mother. All of the 10 exons of the SLC22A5 gene were amplified by PCR and subjected to Sanger sequencing. The amniotic fluid sample was also subjected to G-banded karyotyping and multiplex ligation-dependent probe amplification (MLPA). RESULTS: A homozygous mutation c.760C>T (p.R254X) of the SLC22A5 gene was detected in the proband. Heterozygous mutation c.760C>T (p.R254X) was also found in other family members including the fetus. The karyotyping and chromosomal microdeletion testing for the amniotic fluid sample were both normal. CONCLUSION: The newly identified homozygous nonsense c.760C>T (p.R254X) mutation of the SLC22A5 gene probably underlies the primary carnitine deficiency of the proband. Genetic counseling and prenatal diagnosis have been provided for this family.

Assessment of fetal cardiomyopathy in early-stage twin-twin transfusion syndrome: comparison between commonly reported cardiovascular assessment scores.

OBJECTIVES: To assess the relationship between commonly reported fetal cardiomyopathy scoring systems in early-stage twin-twin transfusion syndrome (TTTS). METHODS: We reviewed retrospectively 100 cases of Quintero Stages I and II TTTS referred to our center for evaluation from 2008 to 2010. The cases were divided into groups of 25, representing each of four grades of TTTS cardiomyopathy as assessed by Cincinnati stage: no cardiomyopathy, Stage IIIa, Stage IIIb and Stage IIIc. Spearman correlation (rs ) was calculated between the Children's Hospital of Philadelphia (CHOP) score, cardiovascular profile score (CVPS), Cincinnati stage and myocardial performance index (MPI). RESULTS: There was a weak correlation between the Cincinnati stage and the CHOP score (rs = 0.36) and CVPS (rs = -0.39), while correlation was strong between the CHOP score and CVPS (rs = -0.72). MPI elevation was concordant with Cincinnati stage more frequently (82% of cases) than were ventricular hypertrophy (43%) or atrioventricular valve regurgitation (28%). 51% of fetuses with minimally elevated CHOP score (0-1) and 48% of fetuses with minimally depressed CVPS (9-10) had significant elevation (Z-score ≥ +3) in right ventricular or left ventricular MPI. CONCLUSIONS: MPI has a strong influence on grading the severity of fetal cardiomyopathy using the Cincinnati stage among fetuses with mild TTTS. Furthermore, significant elevation of the MPI is common among fetuses with mild disease as assessed by the CHOP score and CVPS. These differences should be understood when assessing and grading cardiomyopathy in TTTS, particularly in early (Quintero Stages I and II) disease.

RNA-binding proteins in heart development.

RNA-binding proteins (RBPs) are key players of posttranscriptional regulation occurring during normal tissue development. All tissues examined thus far have revealed the importance of RBPs in the regulation of complex networks involved in organ morphogenesis, maturation, and function. They are responsible for controlling tissue-specific gene expression by regulating alternative splicing, mRNA stability, translation, and poly-adenylation. The heart is the first organ form during embryonic development and is also the first to acquire functionality. Numerous remodeling processes take place during late cardiac development since fetal heart first adapts to birth and then undergoes a transition to adult functionality. This physiological remodeling involves transcriptional and posttranscriptional networks that are regulated by RBPs. Disruption of the normal regulatory networks has been shown to cause cardiomyopathy in humans and animal models. Here we review the complexity of late heart development and the current information regarding how RBPs control aspects of postnatal heart development. We also review how activities of RBPs are modulated adding complexity to the regulation of developmental networks.

Prevalence and progression of recipient-twin cardiomyopathy in early-stage twin-twin transfusion syndrome.

OBJECTIVE: The management of twin-twin transfusion syndrome (TTTS) in its early stages (Quintero Stages I and II) is controversial. We describe the prevalence, severity, incidence and rate of progression of recipient-twin cardiomyopathy in Stages I and II TTTS. METHODS: Among 451 cases of TTTS evaluated between 2004 and 2009, 123 (27.3%) cases of Stages I and II were reviewed. Echocardiography was used to 'upstage' cases based on the presence or absence of mild (IIIA), moderate (IIIB), or severe (IIIC) recipient cardiomyopathy. Progression was defined by worsening in the degree of recipient-twin cardiomyopathy from initial presentation or failure to respond to amnioreduction. Outcome data included progression of recipient-twin cardiomyopathy, treatment and survival to birth. Data were compared by the chi-square, Fisher's exact test or t-test as appropriate. RESULTS: Seventy-seven of 123 (62.6%) cases were Quintero Stage I and 46/123 (37.4%) Quintero Stage II. Eighty (65.0%) were upstaged to Cincinnati Stage IIIA (n = 25), IIIB (n = 23) or IIIC (n = 32). Management included observation in 11 (8.9%), amnioreduction in 26 (21.1%), amnioreduction followed by selective fetoscopic laser photocoagulation (SFLP) in 43 (35.0%) and primary SFLP in 43 (35.0%). Of 80 cases managed by observation or amnioreduction initially, 43 (53.8%) progressed within a mean duration of 1.4 ± 1.5 weeks. The incidence of progression increased significantly as degree of recipient-twin cardiomyopathy at presentation worsened: Stage I, 9/27 (33.3%); Stage II, 8/15 (53.3%); Stage IIIA, 8/16 (50.0%); Stage IIIB, 10/10 (100%); and Stage IIIC, 8/12 (66.7%) (χ(2) = 14, P < 0.01). Overall fetal survival was 205 out of 244 (84.0%). Fetal survival with observation only was 81.8% (18/22), with amnioreduction only it was 92.3% (48/52), with initial observation or amnioreduction followed by SFLP it was 86.9% (73/84) and with primary SFLP it was 76.7% (66/86). CONCLUSION: Echocardiography demonstrates a high incidence of recipient-twin cardiomyopathy in early-stage TTTS. The more advanced the recipient-twin cardiomyopathy is, the more likely is progression to occur during observation or following amnioreduction.

Cardiac morbidity in twin-twin transfusion syndrome?

Twin-to-twin transfusion syndrome (TTTS) affects about 10% of monochorionic pregnancies and develops when uncompensated unidirectional blood flow from one twin ('donor') to the other ('recipient') causes circulatory imbalance. The cardiac effect of the underlying hypervolemia or endocrine dysregulation, or both, manifests in the recipient as echocardiographic findings of the syndrome-related cardiomyopathy. The Quintero staging system for TTTS has recently been questioned, because more refined measurement of cardiac function may improve evaluation of disease severity and prediction of outcome. Much has been done to increase survival and diminish the cardiac morbidity associated with TTTS. The purpose of this paper was to review the literature on cardiac morbidity associated this syndrome.

Assessment of fetal myocardial deformation using speckle tracking techniques.

OBJECTIVE: To report the current status of speckle tracking techniques in evaluation of fetal myocardial deformation. METHODS: A variety of non-Doppler ultrasound methods are available using offline analysis of standard four-chamber and short axis views of the heart. RESULTS: Most reports have used techniques developed for the measurement of strain and strain rate in the adult heart and produced conflicting descriptions of gestational changes in strain. Myocardial velocities usually reflect mean modal velocities and are lower than the peak velocities obtained using Doppler techniques. CONCLUSIONS: In the fetus, most current methods of acquisition result in frame rates that are too low, and the fetal heart size is too small to achieve reliable measures of fetal myocardial deformation.

Evaluation of conventional Doppler fetal cardiac function parameters: E/A ratios, outflow tracts, and myocardial performance index.

Structural evaluation of the fetal heart is well established. Functional evaluation using pulsed-wave Doppler may also be performed. E/A ratios express the relationship between the maximal velocities of the E and A waveforms of ventricular filling. In normal fetuses, E/A ratios are usually <1 but show a constant increment during gestation, mainly related to the increment of the E wave. In intrauterine growth restriction (IUGR) fetuses, E/A ratios are lower compared to values in normally grown fetuses at the same gestational age. Cardiac outflows provide information on the time-velocity integral that, combined with the vessel area, allows calculation of the left and right cardiac outputs. In normal fetuses there is a predominance of the right ventricle (55-60%) in contributing to the combined cardiac output. In IUGR fetuses this predominance shifts to the left ventricle in order to increase the flow to the upper part of the fetal body and brain. The myocardial performance index (MPI) also provides information on systolic and diastolic cardiac function. The MPI is an early and consistent marker of cardiac dysfunction which becomes altered in early stages of chronic hypoxia or in cases with cardiac overload such as in twin-to-twin transfusion syndrome.

Myocardial motion and deformation: What does it tell us and how does it relate to function?

The assessment of cardiac pump function and the potential of local myocardium to contribute to the overall performance are of great importance in many cardiovascular abnormalities. Assessing intrinsic cardiac function requires obtaining information on the true contractility of the heart muscle, assessed locally but interpreted in the context of its contribution to the global ejection performance and potential to adapt to changing circumstances. Contemporary imaging techniques offer the possibility of noninvasive quantification of myocardial deformation. These new clinical tools are attractive to use for the assessment of ventricular function. However, it is of great importance to understand cardiac mechanics - a complex interplay between the tissue structure/shape, force development, and interaction with the environment/neighbors - to interpret alterations in deformation and to extract clinically relevant conclusions. The combination of insight into the measurement techniques and their limitations, together with knowledge of myocardial mechanics and physiology, opens new perspectives to improve the assessment and management of fetal, pediatric, and adult patients.

Myocardial strain abnormalities in fetal congenital heart disease assessed by speckle tracking echocardiography.

OBJECTIVES: To compare myocardial deformation patterns in fetuses with congenital heart disease (CHD) with our reference range using speckle tracking echocardiography. METHODS: We prospectively stored and analyzed 4-chamber loops of 28 fetuses with CHD (median gestation 27 weeks, range 20.9-37.0). The peak longitudinal left (LVs) and right (RVs) ventricular free wall Lagrangian strain and LV/RV strain ratio were measured from Syngo VVI software- (Siemens) derived original coordinates. Strain values from the first examination were compared with normative data from the same population using ANOVA with post hoc tests and serial examinations described in 14 fetuses. RESULTS: Simple shunt lesions (0.82) and shunts with pulmonary stenosis or atresia (0.93) had reduced mean LV/RV strain ratios compared to normal fetuses (1.01; 95% CI 0.97-1.05). Fetuses with hypoplastic left heart had the lowest (0.29), and those with Ebstein the highest (1.55), LV:RV ratio. Serial measurements showed increased LVs in aortic coarctation and aortic stenosis, but not in one developing important mitral regurgitation. Increased right ventricular loading in a fetus developing pulmonary regurgitation was associated with increasing RVs. CONCLUSIONS: Myocardial strain reflects the changing physiology of fetal CHD. Speckle tracking might be a useful tool to study the progress of myocardial function in affected fetuses.

Fetal cardiac function: M-mode and 4D spatiotemporal image correlation.

Fetal cardiac function has been shown to be a marker of disease severity in many conditions, including intrauterine growth restriction, congenital heart defects or disease (CHD), twin-to-twin transfusion syndrome, idiopathic hydrops, fetal arrhythmias, and others. It is often targeted for evaluation of patient management, for providing complete and accurate diagnoses in CHD, for patient counseling, or in referring for fetal cardiac interventions. In this review we will describe the use of M-mode and 4D spatiotemporal image correlation in fetal cardiac evaluation, the parameters that can be measured, and their application to clinical practice.

Fetal cardiac function: technical considerations and potential research and clinical applications.

Fetal echocardiography was initially used to detect structural anomalies but has more recently also been proposed to assess fetal cardiac function. This review summarizes technical issues and limitations in fetal cardiac function evaluation, as well as its potential research and clinical applications. Functional echocardiography has been demonstrated to select high-risk populations and to be associated with outcome in several fetal conditions including intrauterine growth restriction, twin-to-twin transfusion syndrome, maternal diabetes, and congenital diaphragmatic hernia. Fetal heart evaluation is challenging due to the smallness and high heart rate of the fetus and restricted access to the fetus far from the transducer. Due to these limitations and differences in cardiac function which are related to fetal maturation, cardiovascular parameters should be validated in the fetus and used with caution. Despite these precautions, in expert hands and with appropriate ultrasound equipment, evaluation of cardiac function is feasible in most fetuses. Functional fetal echocardiography is a promising tool that may soon be incorporated into clinical practice. Research is warranted to further refine the contribution of fetal cardiac assessment to the diagnosis, monitoring, or prediction of outcomes in various fetal conditions.

Speckle tracking-derived myocardial tissue deformation imaging in twin-twin transfusion syndrome: differences in strain and strain rate between donor and recipient twins.

OBJECTIVES: Twin-twin transfusion syndrome (TTTS) is a complex disorder with altered cardiovascular loading conditions that affects both donors and recipients. Myocardial tissue deformation analysis using vector velocity imaging is an angle-independent, speckle-tracking technique which can assess myocardial mechanics and may provide insight into cardiac dysfunction in TTTS. METHODS: Digital dynamic two-dimensional four-chamber views were interrogated offline. Images were acquired utilizing standard video frame rates (30 frames/s). The global longitudinal strain, systolic strain rate, and diastolic strain rate were measured in the left (LV) and right ventricles (RV) of 25 fetal pairs with TTTS and compared to 25 gestational age-matched normal controls. Pulsatility indices for the umbilical artery and middle cerebral artery were measured. RESULTS: The gestational age at evaluation was 20.5 ± 1.3 weeks. The donor LV systolic strain rate was higher, while the donor RV diastolic strain rate was significantly lower, than control values. The recipient longitudinal strain, systolic strain rate, and diastolic strain rate were significantly lower for both LV and RV in comparison to controls. The donor umbilical artery pulsatility index was higher than control values (1.92 ± 0.45 vs. 1.41 ± 0.25, p < 0.001), while the donor middle cerebral artery pulsatility index was lower (1.46 ± 0.28 vs. 1.87 ± 0.21). Recipient umbilical artery and middle cerebral artery pulsatility indices were no different than control values. CONCLUSIONS: In TTTS, both the donor and the recipient exhibit abnormalities of myocardial tissue deformation with ventricle-specific changes evident based on loading conditions. Donor LV systolic function is hyperdynamic due to hypovolemia and selective ejection into a low-resistance cerebrovascular circuit while the donor RV selectively ejects into a high-resistance placental circuit. Recipient RV and LV are both globally depressed with systolic and diastolic dysfunction. Further prospective validation of our findings using high frame rate analysis is indicated.

Profiling fetal cardiac function in twin-twin transfusion syndrome.

OBJECTIVES: Cardiomyopathy in the recipient twin is a marker of severity in twin-twin transfusion syndrome (TTTS), making it a potentially valuable tool for staging the disease. This study aimed to provide a quantitative description of cardiac function in the recipient twin. METHODS: Consecutive monochorionic pregnancies complicated with TTTS and treated by percutaneous laser coagulation underwent fetal echocardiography before surgery. An unsupervised classification analysis was conducted to identify groups of twins with similar cardiac profiles. The predictive value of the recipient twin's preoperative cardiac function based on these profiles was assessed, using perinatal death of at least one twin as the main outcome. The cardiac function profiles that we identified were compared with the current Quintero staging. RESULTS: A total of 107 pregnancies were included, with six of these lost to follow-up; 63/107 complete cases were available for multivariate description of the recipient's cardiac function. Three different preoperative cardiac profiles were identified with increasing right and left myocardial performance index, decreasing right and left shortening fraction, and increasing ductus venosus pulsatility index. Although the three groups represented progressive stages of the syndrome-related cardiomyopathy, no correlation was found with pregnancy outcome. Of Quintero Stage 1 cases, 55% showed significant alterations of cardiac function in the recipient twin. CONCLUSIONS: Progressive cardiomyopathy can be assessed quantitatively in the recipient twin and does not influence pregnancy outcome when fetoscopic laser coagulation is the first-line treatment. Compared with the current staging, cardiac profiling allows discrimination of cases with significant myocardial dysfunction.

Reversible foetal cerebral ventriculomegaly and cardiomyopathy under chemotherapy for maternal AML.

BACKGROUND: Leukaemia in pregnancy is a rare complication demanding a multidisciplinary approach and careful management to handle potential complications and cope with ethical dilemmas. PATIENT AND METHODS: We report on a patient with acute myeloid leukaemia (AML) relapse in 22 weeks of gestation who received chemotherapy with cytarabine and mitoxantrone, as well as fludarabine, cytarabine, idarubicin, and gemtuzumabozogamicin. We describe findings on regular ultrasound examinations and successful management of complications. RESULTS: The foetus developed signs of anthracycline-induced cardiomyopathy, transient cerebral ventriculomegaly, anaemia, and intrauterine growth restriction. The child was delivered by Caesarean section at 33 + 1 weeks of gestation. The newborn showed no congenital malformations. CONCLUSION: This case report confirms that chemotherapy for treatment of AML can be applied in the second trimester of pregnancy under close and careful maternal and foetal monitoring.

Fhod1, an actin-organizing formin family protein, is dispensable for cardiac development and function in mice.

The formin family proteins have the ability to regulate actin filament assembly, thereby functioning in diverse cytoskeletal processes. Fhod3, a cardiac member of the family, plays a crucial role in development and functional maintenance of the heart. Although Fhod1, a protein closely-related to Fhod3, has been reported to be expressed in cardiomyocytes, the role of Fhod1 in the heart has still remained elusive. To know the physiological role of Fhod1 in the heart, we disrupted the Fhod1 gene in mice by replacement of exon 1 with a lacZ reporter gene. Histological lacZ staining unexpectedly revealed no detectable expression of Fhod1 in the heart, in contrast to intensive staining in the lung, a Fhod1-containing organ. Consistent with this, expression level of the Fhod1 protein in the heart was below the lower limit of detection of the present immunoblot analysis with three independent anti-Fhod1 antibodies. Homozygous Fhod1-null mice did not show any defects in gross and histological appearance of the heart or upregulate fetal cardiac genes that are induced under stress conditions. Furthermore, Fhod1 ablation did not elicit compensatory increase in expression of other formins. Thus, Fhod1 appears to be dispensable for normal development and function of the mouse heart, even if a marginal amount of Fhod1 is expressed in the heart.

Waiting before birth: outcomes after fetal listing for heart transplantation.

Following fetal diagnosis of a profound heart defect, transplantation (HTx) is an alternative to pregnancy termination or neonatal surgical palliation. Retrospective review of the cardiac and transplant databases of fetal listings for HTx between 1990 and July 2006 was undertaken to describe outcomes after listing. We identified 26 fetal listings (of 269 total listings). Diagnoses included congenital heart disease (n = 24) and cardiomyopathy (n = 2). Seven patients were delisted after birth: in five cases parents opted for surgical palliation, two clinically improved. One patient died wait-listed (stillborn). Time wait-listed as a fetus ranged from 1-41 days (median 19 days). Eighteen patients underwent HTx (median weight 2.8 kg, range 2.1-10.9 kg); median days wait-listed after birth was 22 (4 h-123 days). Two fetuses were surgically delivered at 36 weeks gestation when a donor organ became available; 11 were transplanted as neonates (<30 days). The median age at HTx was 1 month (4 h-2.6 months). Fetal listing for HTx increases the potential window of opportunity for a donor organ to become available; patients had low wait-list mortality and a fair intermediate-term outcome. Well-defined criteria for eligibility for fetal listing and priority allocation to infants over fetuses seem rational approaches for centers that offer fetal listing.