Dysregulated endocardial TGFß signaling and mesenchymal transformation result in heart outflow tract septation failure.

Heart outflow tract septation in mouse embryos carrying mutations in retinoic acid receptor genes fails with complete penetrance. In this mutant background, ectopic TGFß signaling in the distal outflow tract is responsible for septation failure, but it was uncertain what tissue was responsive to ectopic TGFß and why this response interfered with septation. By combining RAR gene mutation with tissue-specific Cre drivers and a conditional type II TGFß receptor (Tgfbr2) allele, we determined that ectopic activation of TGFß signaling in the endocardium is responsible for septation defects. Ectopic TGFß signaling results in ectopic mesenchymal transformation of the endocardium and thereby in improperly constituted distal OFT cushions. Our analysis highlights the interactions between myocardium, endocardium, and neural crest cells in outflow tract morphogenesis, and demonstrates the requirement for proper TGFß signaling in outflow tract cushion organization and septation.

Deficiency in the mouse mitochondrial adenine nucleotide translocator isoform 2 gene is associated with cardiac noncompaction.

The mouse fetal and adult hearts express two adenine nucleotide translocator (ANT) isoform genes. The predominant isoform is the heart-muscle-brain ANT-isoform gene 1 (Ant1) while the other is the systemic Ant2 gene. Genetic inactivation of the Ant1 gene does not impair fetal development but results in hypertrophic cardiomyopathy in postnatal mice. Using a knockin X-linked Ant2 allele in which exons 3 and 4 are flanked by loxP sites combined in males with a protamine 1 promoter driven Cre recombinase we created females heterozygous for a null Ant2 allele. Crossing the heterozygous females with the Ant2(fl), PrmCre(+) males resulted in male and female ANT2-null embryos. These fetuses proved to be embryonic lethal by day E14.5 in association with cardiac developmental failure, immature cardiomyocytes having swollen mitochondria, cardiomyocyte hyperproliferation, and cardiac failure due to hypertrabeculation/noncompaction. ANTs have two main functions, mitochondrial-cytosol ATP/ADP exchange and modulation of the mitochondrial permeability transition pore (mtPTP). Previous studies imply that ANT2 biases the mtPTP toward closed while ANT1 biases the mtPTP toward open. It has been reported that immature cardiomyocytes have a constitutively opened mtPTP, the closure of which signals the maturation of cardiomyocytes. Therefore, we hypothesize that the developmental toxicity of the Ant2 null mutation may be the result of biasing the cardiomyocyte mtPTP to remain open thus impairing cardiomyocyte maturation and resulting in cardiomyocyte hyperproliferation and failure of trabecular maturation. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.

Giant chorioangioma treated in utero via laser of feeding vessels with subsequent development of multifocal infantile hemangiomas.

We report a case of a giant placental chorioangioma (15.6 cm diameter) complicated by polyhydramnios and severe fetal heart failure. Fetoscopic laser occlusion of a dominant feeding vessel was performed at 29 weeks' gestation and partial devascularization was achieved. In the 33rd week of the pregnancy, the decision was made to preemptively deliver the fetus due to persistent signs of fetal cardiac failure. After birth, the infant developed multifocal infantile hemangiomas with extracutaneous involvement. We posit that the development of infantile hemangiomas may be linked to the presence of the large chorioangioma. Further study is required to ascertain if fetal treatment of the chorioangioma may have been an exacerbating factor.

Epigenetics in cardiac development, function, and disease.

Substantial new knowledge has accrued, over the past few years, concerning the epigenetic regulation of heart development and disease. Epigenetic mechanisms comprise DNA methylation, ATP-dependent chromatin remodeling, histone modifications, and non-coding RNAs. Many of these processes have been ascertained to influence the tight spatiotemporal control of gene expression during cardiac development. Nevertheless, the relative contribution of each mechanism and their potentially complex interplay remain largely unexplored. Cardiac development and disease are linked through the reactivation of fetal genes upon cardiac hypertrophy and failure. In cardiac disease, changes in gene expression are accompanied and influenced by distinct changes in histone modifications. Detailed knowledge about the epigenetic pathways of cardiac development and function is expected ultimately to lead to novel therapeutic strategies for heart disease and regenerative medicine.

Minimally invasive therapy for fetal sacrococcygeal teratoma: case series and systematic review of the literature.

OBJECTIVE: Large solid sacrococcygeal teratomas (SCT) can cause high-output cardiac failure and fetal or neonatal death. The aim of this study was to describe the outcomes of minimally invasive antenatal procedures for the treatment of fetal SCT. METHODS: A case review was performed of five fetuses with a large SCT treated antenatally using minimally invasive techniques, and a systematic literature review on fetal therapy for solid SCTs was carried out. RESULTS: Five women were referred between 17 + 5 and 26 + 4 weeks' gestation for a large fetal SCT with evidence of fetal cardiac failure. Vascular flow to the tumors was interrupted by fetoscopic laser ablation (n = 1), radiofrequency ablation (RFA; n = 2) or interstitial laser ablation ± vascular coiling (n = 2). There were two intrauterine fetal deaths. The other three cases resulted in preterm labor within 10 days of surgery. One neonate died. Two survived without procedure-related complications but had long-term morbidity related to prematurity. The systematic literature review revealed 16 SCTs treated minimally invasively for (early) hydrops. Including our cases, six of 20 hydropic fetuses survived after minimally invasive therapy (30%). Survival after RFA or interstitial laser ablation was 45% (5/11). Of 12 fetuses treated for SCT without obvious hydrops and for which perinatal survival data were available, eight (67%) survived. Mean gestational age at delivery after minimally invasive therapy was 29.7 ± 4.0 weeks. Survival after open fetal surgery in hydropic fetuses was 6/11 (55%), with a mean gestational age at delivery of 29.8 ± 2.9 weeks. CONCLUSIONS: Fetal therapy can potentially improve perinatal outcomes for hydropic fetuses with a solid SCT, but is often complicated by intrauterine death and preterm birth.

Antenatal management of recurrent fetal goitrous hyperthyroidism associated with fetal cardiac failure in a pregnant woman with persistent high levels of thyroid-stimulating hormone receptor antibody after ablative therapy.

High titer of maternal thyroid-stimulating hormone receptor antibody (TRAb) in patients with Graves' disease could cause fetal hyperthyroidism during pregnancy. Clinical features of fetal hyperthyroidism include tachycardia, goiter, growth restriction, advanced bone maturation, cardiomegaly, and fetal death. The recognition and treatment of fetal hyperthyroidism are believed to be important to optimize growth and intellectual development in affected fetuses. We herein report a case of fetal treatment in two successive siblings showing in utero hyperthyroid status in a woman with a history of ablative treatment for Graves' disease. The fetuses were considered in hyperthyroid status based on high levels of maternal TRAb, a goiter, and persistent tachycardia. In particular, cardiac failure was observed in the second fetus. With intrauterine treatment using potassium iodine and propylthiouracil, fetal cardiac function improved. A high level of TRAb was detected in the both neonates. To the best of our knowledge, this is the first report on the changes of fetal cardiac function in response to fetal treatment in two siblings showing in utero hyperthyroid status. This case report illustrates the impact of prenatal medication via the maternal circulation for fetal hyperthyroidism and cardiac failure.

Doppler sonographic evaluation of arteriovenous shunt flow in a fetus with dural sinus malformation.

Dural sinus malformation (DSM) is a rare congenital malformation characterized by a dilated dural sinus pouch. We present a case of prenatally diagnosed DSM and propose a parameter to predict poor fetal outcome. Detailed ultrasonography at 26 weeks of our patient showed an intracranial cyst in the left posterior fossa. Color Doppler study indicated an arteriovenous shunt within the cyst with increased blood flow velocity. Based on these findings, fetal DSM with arteriovenous shunt was diagnosed. Because of fetal hydrops with high-output cardiac failure and maternal pregnancy-induced hypertension, labor was induced at 32 weeks and resulted in stillbirth. In conclusion, based on the present case, we can deduce that color Doppler study is useful for prenatal diagnosis of DSM with arteriovenous shunt and that a high-flow velocity to the cystic lesion is a possible predictor of hydropic change in such fetuses.

Balloon valvuloplasty for critical aortic stenosis in a fetus: a case report.

The mortality and morbidity of fetal aortic stenosis (AS) depend on the degree of the hemodynamic effects of the stenosis, and left ventricular (LV) adaptation, development and function during fetal life. In the case of critical AS, the development of hydrops and death in utero are well recognized entities. A 23-week gestation fetus was diagnosed with critical severe AS, cardiomegaly, a dilated LV with very poor contractility, and mitral regurgitation. There was a reversal of flow in the aortic arch through the ductus arteriosis and a reversed a-wave in the ductus venosus on Doppler examination. The fetus had hydrops with ascites, and massive scalp, face and skin edema. Fetal amniocentesis was normal. Aortic valvuloplasty was performed under general anesthesia and echocardiographic guidance. Pericardial effusion was not observed after the procedure. However, LV function could not be ameliorated and continued to diminish. There was no cardiac activity in the fetus two hours after the intervention. Aortic valvuloplasty in utero for AS is technically feasible. Mortality is mainly associated with technical errors, LV function, and the degree of endofibroelastosis in the effected fetuses.

Maternal administration of tadalafil improves fetal ventricular systolic function in a Hey2 knockout mouse model of fetal heart failure.

BACKGROUND: There is no established transplacental treatment for heart failure (HF) in utero, and no animal models or experimental systems of fetal HF have been established. This study aimed to investigate the effect of maternal tadalafil administration on fetal cardiovascular function and uteroplacental circulation in a murine model of fetal HF. METHODS AND RESULTS: We first used an ultra-high-frequency ultrasound imaging system in utero and demonstrated that Hey2-/- embryos had worsening right ventricular hypoplasia and marked left ventricular (LV) dilatation as gestation progressed. In both ventricles, fractional shortening (FS) and the E/A ratio were significantly lower in Hey2-/- embryos than in wild-type embryos, indicating that the embryos can be used as a murine model of fetal HF. Subsequently, we evaluated the effect of tadalafil treatment (0.04 or 0.08 mg/ml; T0.04 or T0.08 groups, respectively) on fetoplacental circulation in Hey2-/- embryos. LV FS was significantly higher in the T0.04 group than in control (P < 0.01), whereas LV dilation, mitral E/A ratio, and umbilical artery resistance index were not significantly different among all groups. The thinness of the LV compacted layer did not differ between the T0.04 and vehicle-treated Hey2-/- embryos. CONCLUSIONS: A phenotype comprising marked dilatation and reduced FS of the left ventricles was identified in Hey2-/- embryos, suggesting these embryos as a murine model of fetal HF. In addition, maternal administration of tadalafil improved LV systolic function without altering LV morphological abnormalities in Hey2-/- embryos. Our findings suggest that tadalafil is a potential agent to treat impaired fetal ventricular systolic function.

HAND1 loss-of-function within the embryonic myocardium reveals survivable congenital cardiac defects and adult heart failure.

AIMS: To examine the role of the basic Helix-loop-Helix (bHLH) transcription factor HAND1 in embryonic and adult myocardium. METHODS AND RESULTS: Hand1 is expressed within the cardiomyocytes of the left ventricle (LV) and myocardial cuff between embryonic days (E) 9.5-13.5. Hand gene dosage plays an important role in ventricular morphology and the contribution of Hand1 to congenital heart defects requires further interrogation. Conditional ablation of Hand1 was carried out using either Nkx2.5 knockin Cre (Nkx2.5Cre) or α-myosin heavy chain Cre (αMhc-Cre) driver. Interrogation of transcriptome data via ingenuity pathway analysis reveals several gene regulatory pathways disrupted including translation and cardiac hypertrophy-related pathways. Embryo and adult hearts were subjected to histological, functional, and molecular analyses. Myocardial deletion of Hand1 results in morphological defects that include cardiac conduction system defects, survivable interventricular septal defects, and abnormal LV papillary muscles (PMs). Resulting Hand1 conditional mutants are born at Mendelian frequencies; but the morphological alterations acquired during cardiac development result in, the mice developing diastolic heart failure. CONCLUSION: Collectively, these data reveal that HAND1 contributes to the morphogenic patterning and maturation of cardiomyocytes during embryogenesis and although survivable, indicates a role for Hand1 within the developing conduction system and PM development.

Outflow tract cushions perform a critical valve-like function in the early embryonic heart requiring BMPRIA-mediated signaling in cardiac neural crest.

Neural crest-specific ablation of BMP type IA receptor (BMPRIA) causes embryonic lethality by embryonic day (E) 12.5, and this was previously postulated to arise from a myocardial defect related to signaling by a small population of cardiac neural crest cells (cNCC) in the epicardium. However, as BMP signaling via cNCC is also required for proper development of the outflow tract cushions, precursors to the semilunar valves, a plausible alternate or additional hypothesis is that heart failure may result from an outflow tract cushion defect. To investigate whether the outflow tract cushions may serve as dynamic valves in regulating hemodynamic function in the early embryo, in this study we used noninvasive ultrasound biomicroscopy-Doppler imaging to quantitatively assess hemodynamic function in mouse embryos with P0-Cre transgene mediated neural crest ablation of Bmpr1a (P0 mutants). Similar to previous studies, the neural crest-deleted Bmpr1a P0 mutants died at approximately E12.5, exhibiting persistent truncus arteriosus, thinned myocardium, and congestive heart failure. Surprisingly, our ultrasound analyses showed normal contractile indices, heart rate, and atrioventricular conduction in the P0 mutants. However, reversed diastolic arterial blood flow was detected as early as E11.5, with cardiovascular insufficiency and death rapidly ensuing by E12.5. Quantitative computed tomography showed thinning of the outflow cushions, and this was associated with a marked reduction in cell proliferation. These results suggest BMP signaling to cNCC is required for growth of the outflow tract cushions. This study provides definitive evidence that the outflow cushions perform a valve-like function critical for survival of the early mouse embryo.

Myocardial smad4 is essential for cardiogenesis in mouse embryos.

Congenital heart diseases are the most commonly observed human birth defects and are the leading cause of infant morbidity and mortality. Accumulating evidence indicates that transforming growth factor-beta/bone morphogenetic protein signaling pathways play critical roles during cardiogenesis. Smad4 encodes the only common Smad protein in mammals, which is a critical nuclear mediator of transforming growth factor-beta/bone morphogenetic protein signaling. The aim of this work was to investigate the roles of Smad4 during heart development. To overcome the early embryonic lethality of Smad4(-/-) mice, we specifically disrupted Smad4 in the myocardium using a Cre/loxP system. We show that myocardial-specific inactivation of Smad4 caused heart failure and embryonic lethality at midgestation. Histological analysis revealed that mutant mice displayed a hypocellular myocardial wall defect, which is likely the primary cause for heart failure. Both decreased cell proliferation and increased apoptosis contributed to the myocardial wall defect in mutant mice. Data presented in this article contradict a previous report showing that Smad4 is dispensable for heart development. Our further molecular characterization showed that expression of Nmyc and its downstream targets, including cyclin D1, cyclin D2, and Id2, were downregulated in mutant embryos. Reporter analysis indicated that the transcriptional activity of the 351-bp Nmyc promoter can be positively regulated by bone morphogenetic protein stimulation and negatively regulated by transforming growth factor-beta stimulation. Chromatin immunoprecipitation analysis revealed that the Nmyc promoter can form a complex with Smad4, suggesting that Nmyc is a direct downstream target of Smad4. In conclusion, this study provides the first mouse model showing that Smad4 plays essential roles during cardiogenesis.

Early detection (9+6 weeks) of cardiac failure in a fetus diagnosed as Turner syndrome by 2D transvaginal ultrasound-guided coelocentesis.

A 28-year-old woman was diagnosed by transvaginal ultrasound at 9+6 weeks with early fetal cardiac failure (hydrothorax and bradycardia). Doppler analysis of ductus venosus showed a negative A-wave pattern. The follow-up sonogram obtained at 11+6 weeks documented a missed abortion. A transvaginal ultrasound-guided coelocentesis was performed under local cervical anesthesia before uterine suction and 8 mL of clear extracoelomic fluid were successfully aspirated. Cytogenetic analysis demonstrated a 45,X karyotype. Ultrasound and Doppler waveform analysis of ductus venosus allowed early diagnosis of fetal cardiac failure. Coelocentesis may be the method of choice for early fetal karyotyping and may be used in the future to induce immunologic tolerance.

Is genomic screening necessary for fetuses who suffer moderate to severe tricuspid regurgitation?: A case report.

RATIONALE: Tricuspid regurgitation (TR) is a frequent finding during echocardiography screening in fetal or neonatal life, which reveals a weak association between TR and cardiac malformation. Except for structural abnormalities, dilated cardiomyopathy (DCM) ranks as the top reason for early child morbidity and mortality among all kinds of cardiomyopathy. In the early fetal stage, cardiac abnormalities detected by early fetal genetic testing followed by abnormalities on ultrasound would provide more valuable information for parents and physicians to make a better therapeutic schedule. PATIENT CONCERNS: A case of severe TR was found via the fetal ultrasound screening. After birth, this child suffered severe heart dysfunction, and echocardiography confirmed a DCM phenotype within a very short time. DIAGNOSIS AND INTERVENTION: A 40-year-old female received routine fetal echocardiographic screening, which demonstrated that the fetus presented severe TR. Six months after birth, the baby experienced severe heart failure, as the EF dropped to 22% with an extremely large LV chamber. The genomic sequence had been determined, and 3 pathogenic gene mutations located in 2 genes, cardiac troponin T (TNNT2) c.548G>A, desmoplakin (DSP) c.3146C>T, and DSP c.5213G>A, were identified. Finally, the patient was diagnosed with DCM. This child received digoxin, hydrochlorothiazide, spironolactone diuresis, captopril, and L-carnitine, and the symptoms of heart failure had been controlled as the patient waited for heart transplantation. OUTCOMES: During the follow-up, the patient still suffered from poor heart function and an enlarged left ventricle. Concomitantly, the parents placed her on a waiting list for heart transplantation. LESSONS: Fetal TR is a common phenomenon, and many studies have indicated that isolated TR is not an appropriate predictor of chromosomal abnormalities or congenital heart defects. However, according to this case, it is urgent to recommend that the mother should take advantage of free fetal DNA analysis in a maternal blood sample to obtain further molecular evidence once fetal echocardiography reveals moderate to severe TR with any maternal high-risk factors for birth defects.

Color M-mode propagation velocity, but not its ratio to early diastolic inflow velocity, changes throughout gestation in normal human fetuses.

OBJECTIVES: Color M-mode propagation velocity (Vp) is a measure of diastolic function in adults and, when combined with early diastolic inflow velocity (E), the ratio E/Vp reflects ventricular filling pressure. Early detection of diastolic compromise may benefit fetal patients at risk for developing heart failure. The objectives of this study were to measure values for Vp and inflow peak E in a group of normal fetuses, to analyze age-dependent alterations in these measurements, and to evaluate the interobserver and intraobserver variability of the measurements. METHODS: Thirty-two normal fetuses at between 20 and 35 weeks' gestation underwent echocardiography. Color M-mode Vp was measured from the four-chamber view for the right (RV) and left (LV) ventricles, and mitral and tricuspid inflow velocities were determined by pulsed-wave Doppler ultrasound. The values obtained were compared with previously reported findings in adults. RESULTS: Adequate tracings were obtainable in 23 patients for the RV and 29 for the LV. Mean Vp values for the RV (15.3 +/- 3.2 cm/s) and LV (20.8 +/- 5.6 cm/s) were lower than normal adult values, and Vp values were significantly lower for the RV than the LV (P < 0.001). Applying Bazett's heart rate correction, values for RV (23.4 +/- 4.8 cm/s) and LV (31.9 +/- 8.7 cm/s) remained lower than normal adult values. There was a linear correlation of Vp with gestational age for the RV (R = 0.69, P < 0.001), and the ratio of E/Vp corrected for heart rate for the RV (1.51 +/- 0.26) remained constant throughout gestation. Interobserver bias was high but intraobserver bias low, at 19 and 1.1%, respectively. CONCLUSIONS: Vp is lower in fetal than in adult life. Vp for the RV changes in a manner indicative of improving diastolic function throughout normal gestation, providing insight into the alterations in diastolic function with gestation that contribute to increases in cardiac output. The use of Vp to assess diastolic function disturbance in fetuses is feasible, but high interobserver variability is problematic.

Prediction of outcome of fetal congenital heart disease using a cardiovascular profile score.

OBJECTIVES: Congestive heart failure in fetuses with congenital heart defects (CHD) is associated with high perinatal mortality. The clinical condition can be characterized by five ultrasound markers that comprise the 10-point cardiovascular profile (CVP) score. Our aim was to assess the value of the CVP score in evaluating the condition and in maintaining surveillance of fetuses with CHD. METHODS: We evaluated retrospectively 131 singleton pregnancies with a diagnosis of fetal CHD, which had been assessed by serial echocardiographic examinations, during which the CVP score was obtained. Fetal and neonatal outcomes, including perinatal mortality and Apgar scores, were assessed. RESULTS: Fetuses with a final CVP score or= 8 (87.5% vs. 15.2% mortality; P < 0.0001, chi square = 24.5). Significance was maintained after controlling for birth weight, lag time between the final examination and delivery and the dichotomized 5-min Apgar score (odds ratio, 22.3; P = 0.024). For low Apgar score and mortality, the CVP score had low sensitivity (0.25 and 0.27, respectively) but high specificity (0.98 and 0.99, respectively). The presence of hydrops and severe cardiomegaly were statistically significantly associated with mortality (P < 0.05). CONCLUSIONS: Fetuses with CHD and a CVP score below 8 are at risk of perinatal death. The CVP score may be used to assess the severity of fetal CHD and to plan perinatal management.

Loss of embryonic neural crest derived cardiomyocytes causes adult onset hypertrophic cardiomyopathy in zebrafish.

Neural crest cells migrate to the embryonic heart and transform into a small number of cardiomyocytes, but their functions in the developing and adult heart are unknown. Here, we show that neural crest derived cardiomyocytes (NC-Cms) in the zebrafish ventricle express Notch ligand jag2b, are adjacent to Notch responding cells, and persist throughout life. Genetic ablation of NC-Cms during embryogenesis results in diminished jag2b, altered Notch signaling and aberrant trabeculation patterns, but is not detrimental to early heart function or survival to adulthood. However, embryonic NC-Cm ablation results in adult fish that show severe hypertrophic cardiomyopathy (HCM), altered cardiomyocyte size, diminished adult heart capacity and heart failure in cardiac stress tests. Adult jag2b mutants have similar cardiomyopathy. Thus, we identify a cardiomyocyte population and genetic pathway that are required to prevent adult onset HCM and provide a zebrafish model of adult-onset HCM and heart failure.

Fetal hemoglobin Bart's hydrops fetalis: pathophysiology, prenatal diagnosis and possibility of intrauterine treatment.

This review aimed at comprehensively summarizing current available reports regarding the ultrasound markers and biomarkers in predicting fetal Hb Bart's disease and evaluate the potential role of cardiac function assessment in a clinical practice. This review involves various methods in prenatal predicting fetal Hb Bart's disease or alpha-thalassemia major and attempts to provide valuable insights regarding the underlying mechanisms responsible for heart failure in Hb Bart's fetuses. Moreover, this information may be used to predict the cardiac function before the development of hydrops fetalis. Finally, the affected Hb Bart's fetus could be the best model of the study on cardiovascular response to fetal anemia, thus the cardiovascular ultrasound and molecular assessment may be helpful in predicting the prognosis or in making a choice in the management of the fetal anemia condition. In conclusion, ultrasound findings especially cardiomegaly and an increase in peak systolic velocity of the middle cerebral artery (MCA-PSV) are helpful in predicting the future hydrops fetalis and ultrasound assessment of fetal cardiac function is potentially helpful in clinical practice. Finally, this review highlights the pathogenesis of hydropic changes secondary to fetal anemia.

Aristolochic Acid induces heart failure in zebrafish embryos that is mediated by inflammation.

Aristolochic Acid (AA) is a component of Chinese herbs that has been found to be toxic to multiple organs in adults. Its toxicity to developing embryos has not been reported. Here, we describe that AA specifically causes heart defects in developing zebrafish embryos in a dosage-dependent manner. The treated embryos are able to develop their hearts normally up to 24 h postfertilization, when cardiac contraction initiates, but begin to show deformation and reduction of the hearts followed by gradual contractility loss and eventually lethality, suggesting that AA is primarily affecting cardiac physiology rather than cardiogenesis. Histological analyses reveal that the AA-treated hearts develop hypertrophy and disorganization of cardiomyocytes and loss of endocardium. By transmission electron microscopy, we observed broken and disorganized cardiac fibers in the AA-treated hearts. AA induces the expression of proinflammation genes, including cox-2, IL-1beta, and others. The AA-induced cardiac defects can be attenuated by the cox-2 antagonist NS398 via reducing the expression of the inflammatory genes. This attenuation could be further enhanced by known heart failure drugs, such as angiotensin-converting enzyme inhibitor and beta-adrenergic receptor antagonist. In contrast, the heart defects are enhanced by a beta-adrenergic receptor agonist. In summary, AA causes profound toxicity to zebrafish embryos that exhibit pathophysiological and pharmacological features resembling those of heart failure in humans and other model organisms, and thus, zebrafish could be a new model for studies on heart failure.