Severe Cardiac Defects Research Articles

HAND factors regulate cardiac lineage commitment and differentiation from human pluripotent stem cells

BackgroundTranscription factors HAND1 and HAND2 (HAND1/2) play significant roles in cardiac organogenesis. Abnormal expression and deficiency of HAND1/2 result in severe cardiac defects. However, the function and mechanism of HAND1/2 in regulating human early cardiac lineage commitment and differentiation are still unclear.MethodsWith NKX2.5eGFP H9 human embryonic stem cells (hESCs), we established single and double knockout cell lines for HAND1 and HAND2, respectively, whose cardiomyocyte differentiation efficiency could be monitored by assessing NKX2.5-eGFP+ cells with flow cytometry. The expression of specific markers for heart fields and cardiomyocyte subtypes was examined by quantitative PCR, western blot and immunofluorescence staining. Microelectrode array and whole-cell patch clamp were performed to determine the electrophysiological characteristics of differentiated cardiomyocytes. The transcriptomic changes of HAND knockout cells were revealed by RNA sequencing. The HAND1/2 target genes were identified and validated experimentally by integrating with HAND1/2 chromatin immunoprecipitation sequencing data.ResultsEither HAND1 or HAND2 knockout did not affect the cardiomyocyte differentiation kinetics, whereas depletion of HAND1/2 resulted in delayed differentiation onset. HAND1 knockout biased cardiac mesoderm toward second heart field progenitors at the expense of first heart field progenitors, leading to increased expression of atrial and outflow tract cardiomyocyte markers, which was further confirmed by the appearance of atrial-like action potentials. By contrast, HAND2 knockout cardiomyocytes had reduced expression of atrial cardiomyocyte markers and displayed ventricular-like action potentials. HAND1/2-deficient hESCs were more inclined to second heart field lineage and its derived cardiomyocytes with atrial-like action potentials than HAND1 single knockout during differentiation. Further mechanistic investigations suggested TBX5 as one of the downstream targets of HAND1/2, whose overexpression partially restored the abnormal cardiomyocyte differentiation in HAND1/2-deficient hESCs.ConclusionsHAND1/2 have specific and redundant roles in cardiac lineage commitment and differentiation. These findings not only reveal the essential function of HAND1/2 in cardiac organogenesis, but also provide important information on the pathogenesis of HAND1/2 deficiency-related congenital heart diseases, which could potentially lead to new therapeutic strategies.

The Tbx20-TLE interaction is essential for the maintenance of the second heart field.

T-box transcription factor 20 (Tbx20) plays a multifaceted role in cardiac morphogenesis and controls a broad gene regulatory network. However, the mechanism by which Tbx20 activates and represses target genes in a tissue-specific and temporal manner remains unclear. Studies show that Tbx20 directly interacts with the Transducin-like Enhancer of Split (TLE) family of proteins to mediate transcriptional repression. However, a function for the Tbx20-TLE transcriptional repression complex during heart development has yet to be established. We created a mouse model with a two amino acid substitution in the Tbx20 EH1 domain, thereby disrupting the Tbx20-TLE interaction. Disruption of this interaction impaired crucial morphogenic events, including cardiac looping and chamber formation. Transcriptional profiling of Tbx20EH1Mut hearts and analysis of putative direct targets revealed misexpression of the retinoic acid pathway and cardiac progenitor genes. Further, we show that altered cardiac progenitor development and function contribute to the severe cardiac defects in our model. Our studies indicate that TLE-mediated repression is a primary mechanism by which Tbx20 controls gene expression.

Survival and factors associated with mortality among infants with anorectal malformation: a population-based study from a middle-income country.

Limited data on the survival of anorectal malformation (ARM) patients from lower- and middle-income countries is available. This retrospective population-based study from the State of Johor, Malaysia, determines the incidence, mortality rate, and survival of ARM patients and factors associated with mortality. Kaplan-Meier survival analysis was used to estimate the survival of ARM patients at 1, 5, and 10years. In addition, multivariate Cox regression analysis was used to analyze mortality-related factors. There were 175 ARM patients among 803,850 live births, giving an overall ARM incidence of 2.2 (95% confidence interval [CI], 1.9 to 2.5) per 10,000 live births. The male-to-female ratio was 1.5:1. There were 122 (69%) non-isolated ARM, of which 41 were Trisomy-21 and 34 had VACTERL association. Seventy-three (42%) had congenital heart disease (CHD), with 38 severe and 35 non-severe CHD. Overall, 33 (19%) patients died, with a median age of death of 5.7months (interquartile range (IQR) 25days to 11.2months). The overall estimated 1-, 5-, and 10-year survival rate for ARM patients was 82% (95% CI, 76-89%), 77% (95% CI, 70-84%), and 77% (95% CI, 70-84%), respectively. Univariate analysis shows that non-isolated ARM, VACTERL association, and severe CHD were associated with mortality. However, only severe CHD is the independent factor associated with mortality, with a hazard ratio of 4.0 (95% CI, 1.9-8.4). Conclusion: CHD is common among ARM patients, and one in five ARM patients had a severe cardiac defect, significantly affecting their survival. What is Known: • VACTERL association and congenital heart disease are common in patient with anorectal malformation. • Low birth weight and prematurity are associated with a lower rate of survival. What is New: • Congenital heart disease is common in ARM patients in a middle-income country. • Severe congenital heart disease plays a significant role in the survival of patients with an anorectal malformation in lower- and middle-income countries.

Infantile Spasms and Developmental Delay: A Case of Miller–Dieker Syndrome

Background: Miller–Dieker syndrome (MDS) is a rare genetic disorder, due to contiguous gene deletion on chromosome 17p13.3, characterized by classical type I lissencephaly, severe developmental delay, seizures, cardiac defects, and dysmorphisms. West syndrome is a severe form of epilepsy with epileptic spasms, hypsarrhythmia in electroencephalogram (EEG), and neuropsychomotor delay. Herein, we describe the neurophysiological and neuroimaging findings of a patient with MDS with associated West syndrome. Clinical Description: A 5-month-old boy was brought with new-onset infantile spasms and a history of delay and some regression in milestones. Facial dysmorphism was noted in the form of a prominent forehead, bitemporal hollowing, short nose with upturned nares, thickened upper lip, long philtrum, low-set ears, and hypertelorism. There was hypotonia of all four limbs. Management and Outcome: An EEG showed hypsarrhythmia, and the magnetic resonance imaging brain revealed hypoplastic sulci with pachygyria and smooth cortical surface of supratentorial brain parenchyma – features suggestive of lissencephaly type 1. Echocardiography showed atrial septal defect and minimal pericardial effusion. Whole-exome sequencing showed a contiguous large heterozygous deletion on chromosome 17 which was suggestive of Miller–Dieker lissencephaly syndrome. Parents were counseled, and the spasms were treated with an injection adrenocorticotropic hormone and oral vigabatrin. Conclusion: Structural brain abnormalities are well-known causes of infantile spasms. MDS is a severe malformative condition, lissencephaly being the hallmark of this disorder. This case report will create awareness among pediatricians regarding this rare condition with a characteristic combination of clinical features, which can be confirmed by brain imaging and genetic analysis.

Loss of Sec-1 Family Domain-Containing 1 (scfd1) Causes Severe Cardiac Defects and Endoplasmic Reticulum Stress in Zebrafish.

Dilated cardiomyopathy (DCM) is a common heart muscle disorder that frequently leads to heart failure, arrhythmias, and death. While DCM is often heritable, disease-causing mutations are identified in only ~30% of cases. In a forward genetic mutagenesis screen, we identified a novel zebrafish mutant, heart and head (hahvcc43), characterized by early-onset cardiomyopathy and craniofacial defects. Linkage analysis and next-generation sequencing identified a nonsense variant in the highly conserved scfd1 gene, also known as sly1, that encodes sec1 family domain-containing 1. Sec1/Munc18 proteins, such as Scfd1, are involved in membrane fusion regulating endoplasmic reticulum (ER)/Golgi transport. CRISPR/Cas9-engineered scfd1vcc44 null mutants showed severe cardiac and craniofacial defects and embryonic lethality that recapitulated the phenotype of hahvcc43 mutants. Electron micrographs of scfd1-depleted cardiomyocytes showed reduced myofibril width and sarcomere density, as well as reticular network disorganization and fragmentation of Golgi stacks. Furthermore, quantitative PCR analysis showed upregulation of ER stress response and apoptosis markers. Both heterozygous hahvcc43 mutants and scfd1vcc44 mutants survived to adulthood, showing chamber dilation and reduced ventricular contraction. Collectively, our data implicate scfd1 loss-of-function as the genetic defect at the hahvcc43 locus and provide new insights into the role of scfd1 in cardiac development and function.

Loss of Sec-1 Family Domain-Containing 1 (Scfd1) Causes Severe Cardiac Defects and Endoplasmic Reticulum Stress in Zebrafish

Loss of Sec-1 Family Domain-Containing 1 (Scfd1) Causes Severe Cardiac Defects and Endoplasmic Reticulum Stress in Zebrafish

Dysregulated H19/Igf2 expression disrupts cardiac-placental axis during development of Silver-Russell syndrome-like mouse models.

Dysregulation of the imprinted H19/IGF2 locus can lead to Silver-Russell syndrome (SRS) in humans. However, the mechanism of how abnormal H19/IGF2 expression contributes to various SRS phenotypes remains unclear, largely due to incomplete understanding of the developmental functions of these two genes. We previously generated a mouse model with humanized H19/IGF2 imprinting control region (hIC1) on the paternal allele that exhibited H19/Igf2 dysregulation together with SRS-like growth restriction and perinatal lethality. Here, we dissect the role of H19 and Igf2 in cardiac and placental development utilizing multiple mouse models with varying levels of H19 and Igf2. We report severe cardiac defects such as ventricular septal defects and thinned myocardium, placental anomalies including thrombosis and vascular malformations, together with growth restriction in mouse embryos that correlated with the extent of H19/Igf2 dysregulation. Transcriptomic analysis using cardiac endothelial cells of these mouse models shows that H19/Igf2 dysregulation disrupts pathways related to extracellular matrix and proliferation of endothelial cells. Our work links the heart and placenta through regulation by H19 and Igf2, demonstrating that accurate dosage of both H19 and Igf2 is critical for normal embryonic development, especially related to the cardiac-placental axis.

45 Using fetal ultrasound to predict developmental outcomes in children born with cardiac defects in Manitoba: A historical cohort study

Abstract Background The cavum septum pellucidum (CSP) is a normal anatomical cavity found in the mid-brain of the fetus and is routinely imaged at the time of mid-pregnancy obstetrical ultrasound as part of anatomic survey. Presence of the CSP reflects intact intrahemispheric connections and an intact corpus callosum. The CSP space then closes by the time of birth or early infancy, however persistence of the CSP into adulthood has been described in those with the schizophrenic phenotype of DiGeorge syndrome. Preliminary work by our group in Manitoba has shown utility in measurement of CSP width to improve non-invasive prenatal diagnosis of DiGeorge syndrome among fetuses with and without conotruncal cardiac defects. However, there exists no information about the relationship between fetal CSP width and future neurodevelopmental outcomes, such as Bayley-III scores, in children with cardiac lesions in the absence of underlying genetic comorbidities. Objectives To determine the relationship between cavum septum pellucidum (CSP) width and neurodevelopment in children born with sever cardiac defects. Design/Methods This was a historical cohort study of children born with cardiac anomalies in Manitoba (2009-2019). Eligible children with developmental pediatric follow-up between ages 18-24 months corrected age were identified using a clinical repository. Post-processing measurement of fetal CSP at mid-gestation using stored obstetrical ultrasounds was performed by two blinded and independent reviewers in a standardized fashion. Ultrasound reports were also reviewed to collate data about routine fetal biometry and imaging data then linked to demographics, birth information, surgical details and neurodevelopmental outcomes (Bayley-III scales). Linear regression models were used to evaluate the relationship between CSP width and Bayley-III scores; inferential statistics were used to compare outcomes between groups (biventricular versus single-ventricle repair). Results 78 of 111 eligible cases had stored ultrasound images and included in the analysis. Most children were delivered at term following vaginal delivery (71%), with normal birthweight and Apgars. Median CSP width was 3.8mm (SD 1.2). There was a range conotruncal cardiac anomalies and 47% required single-ventricle repair. There was no obvious relationship between CSP width and Bayley-III motor (p=0.932) or cognitive domains (p0.686), however there was a trend towards larger CSP and higher Bayley-III language scores (p=0.049). Conclusion The influence of the deoxygenated blood on the developing fetal brain in modifying outcomes for children with severe cardiac defects needs future study to improve postnatal development in this high-risk group.

An improved congenital heart assessment tool: a quality improvement outcome.

CHD was the most prevalent congenital anomaly (60.9 per 10,000, 95% CI 59.0-62.8) in England in 2018, with 1767 babies born with severe cardiac defects. The 30-day survival rates for complex procedures continue to improve; however despite care advances, the early post-operative period and first year of life remain a critical time for these infants. The Congenital Heart Assessment Tool was developed to support parental decision-making, standardise care provision, improve communication, and the safety and quality of care. To further evaluate the Congenital Heart Assessment Tool. A four centre collaborative mixed-methods quality improvement project funded by The Health Foundation, involving eight phases conducted during 2016-2018. Phases six to eight (clinical simulation exercise, parent workshop, and updated tool) are reported in this paper. Four themes emerged from the clinical simulation exercise (phase six) including: improving documentation; preparation of parents; preparation of health care professionals; and communication. One main theme emerged from the parent workshop (phase seven): "what parents know versus what professionals know [about CHD]". These phases further validated the effectiveness of the CHATm in terms of triggering amber and red indicators and demonstrated parents' ability to identify deterioration in their infant's clinical condition. Recommendations arising from the quality improvement project enabled the project team to create an updated version of the Congenital Heart Assessment Tool, CHAT2.

Factors Affecting Psychological and Health-Related Quality-of-Life Status in Children and Adolescents with Congenital Heart Diseases.

Congenital heart disease (CHD), a severe cardiac defect in children, has unclear influences on young patients. We aimed to find the impacts of differently structure heart defects and various treatments on psychology and health-related quality of life (HRQoL) in CHD children and adolescents. CHD patients aged between 6 and 18 years old visited our hospital from 1 May 2018 to 31 September 2018, and their principal caregivers were asked to participate. We used two validated questionnaires, Children Depression Inventory-TW (CDI-TW) and Child Health Questionnaire—Parent Form 50 (CHQ-PF 50), to evaluate CHD patients’ psychological and HRQoL conditions. Participants were grouped based on their cardiac defects and previous treatments. We analyzed the results via summary independent-samples t-test with post hoc Bonferroni correction and multivariant analysis. Two hundred and seventy-seven children and their principal caregivers were involved. There was no apparent depressive condition in any group. Single cardiac defect patients exhibited similar HRQoL to controls; simultaneously, those with cyanotic heart disease (CyHD), most multiple/complex CHDs children and adolescents, and those who received invasive treatments had poorer HRQoL. CyHD impacted the most on patients’ psychological and HRQoL status. Patients with sole cardiac defect could live near-normal lifes; on the other hand, CyHD had the worst effects on patients’ psychology and HRQoL.

Severe cardiac defect in Cornelia de Lange syndrome from a novel SMC1A variant.

Severe cardiac defect in Cornelia de Lange syndrome from a novel SMC1A variant.

Patau’s syndrome ultrasonographic and morphological features of a near term live birth case

We report a near term live birth of a child prenatally diagnosed with Patau’s syndrome, rare case reaching this gestational age. Despite the acknowledgement of the poor fetal prognostic the parents chose to accept the natural course of the affected pregnancy, decision based on religious considerations. Alobar subtype of holoprosencephaly associating facial dysmorphism along with severe cardiac and limb defects and ambiguous genitalia were the main ultrasonographic and clinical findings. We describe a particular phonotypical association for a full aneuploidy that have been early prenatal diagnosed.

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.

Congenital anomalies in children with postneonatally acquired cerebral palsy: an international data linkage study.

To describe the major congenital anomalies present in children with postneonatally acquired cerebral palsy (CP), and to compare clinical outcomes and cause of postneonatally acquired CP between children with and without anomalies. Data were linked between total population CP and congenital anomaly registers in five European and three Australian regions for children born 1991 to 2009 (n=468 children with postneonatally acquired CP; 255 males, 213 females). Data were pooled and children classified into mutually exclusive categories based on type of congenital anomaly. The proportion of children with congenital anomalies was calculated. Clinical outcomes and cause of postneonatally acquired CP were compared between children with and without anomalies. Major congenital anomalies were reported in 25.6% (95% confidence interval [CI] 21.7-29.9) of children with postneonatally acquired CP. Cardiac anomalies, often severe, were common and present in 14.5% of children with postneonatally acquired CP. Clinical outcomes were not more severe in children with congenital anomalies than those without anomalies. Cause of postneonatally acquired CP differed with the presence of congenital anomalies, with cerebrovascular accidents predominating in the anomaly group. Congenital anomalies were likely associated with cause of postneonatally acquired CP in 77% of children with anomalies. In this large, international study of children with postneonatally acquired CP, congenital anomalies (particularly cardiac anomalies) were common. Future research should determine specific causal pathways to postneonatally acquired CP that include congenital anomalies to identify opportunities for prevention. One-quarter of children with postneonatally acquired cerebral palsy (CP) have a major congenital anomaly. Cardiac anomalies, often severe, are the most common anomalies. Causes of postneonatally acquired CP differ between children with and without congenital anomalies.

Jejuno-ileal atresia: evaluation of the efficacy of laparoscopic approach

Jejuno-ileal atresia is a main cause of neonatal intestinal obstructions, and minimal access technique is gaining popularity. Aim of this study was to perform systematic review of laparoscopic approach with regards its management efficacy. Pubmed® was searched using terms ‘jejunal’, ‘jejuno-intestinal atresia’, ‘laparoscopic’ or ‘laparoscopic-assisted’. Data collected included gender, age, weight, comorbidities, surgical technique, duration of surgery, complications, reoperation, mortality, parenteral feeding time. 5 articles (2004–2020) met the inclusion criteria with 63 neonates. Mean weight was 2.6 kg. There were n = 16 comorbidities: cardiac anomalies (n = 5), Meckel’s diverticulum (n = 2), meconium peritonitis (n = 4), unknown (n = 5). All patients had laparoscopic-assisted surgery, out of which n = 25 were single-port approach. Conversion was reported in n = 4 cases due to meconium ileus (n = 2), or significantly dilated bowel (n = 2). There were n = 7 complications (n = 1 sepsis, n = 2 anastomotic leaks, n = 1 cholestasis, n = 3 adhesive ileus). Two reoperations were necessary because of anastomotic dehiscence (n = 1) and adhesive ileus (n = 1). Mean parenteral feeding time was 13 days. There were three lethal outcomes, due to sepsis after anastomotic leak (n = 1), severe cardiac defect (n = 1), pneumonia and adhesive ileus (n = 1). Laparoscopic-assisted is opted for jejuno-ileal atresia when minimal access approach is preferred. It is fast and feasible technique, which offers better cosmesis, may result shorter length of operation and recovery. There is > 10% complication rate, which rarely require reoperation. Limitation of this approach are low weight babies with associated anomalies, or significantly dilated proximal bowels. These remain the main concern for laparoscopic-assisted surgery, which require open approach or conversion.

BET bromodomain inhibition attenuates cardiac phenotype in myocyte-specific lamin A/C-deficient mice.

Mutation in the LMNA gene, encoding lamin A/C, causes a diverse group of diseases called laminopathies. Cardiac involvement is the major cause of death and manifests as dilated cardiomyopathy, heart failure, arrhythmias, and sudden death. There is no specific therapy for LMNA-associated cardiomyopathy. We report that deletion of Lmna in cardiomyocytes in mice leads to severe cardiac dysfunction, conduction defect, ventricular arrhythmias, fibrosis, apoptosis, and premature death within 4 weeks. The phenotype is similar to LMNA-associated cardiomyopathy in humans. RNA sequencing, performed before the onset of cardiac dysfunction, led to identification of 2338 differentially expressed genes (DEGs) in Lmna-deleted cardiomyocytes. DEGs predicted activation of bromodomain-containing protein 4 (BRD4), a regulator of chromatin-associated proteins and transcription factors, which was confirmed by complementary approaches, including chromatin immunoprecipitation sequencing. Daily injection of JQ1, a specific BET bromodomain inhibitor, partially reversed the DEGs, including those encoding secretome; improved cardiac function; abrogated cardiac arrhythmias, fibrosis, and apoptosis; and prolonged the median survival time 2-fold in the myocyte-specific Lmna-deleted mice. The findings highlight the important role of LMNA in cardiomyocytes and identify BET bromodomain inhibition as a potential therapeutic target in LMNA-associated cardiomyopathy, for which there is no specific effective therapy.

Ageing-associated increase in SGLT2 disrupts mitochondrial/sarcoplasmic reticulum Ca2+ homeostasis and promotes cardiac dysfunction.

The prevalence of death from cardiovascular disease is significantly higher in elderly populations; the underlying factors that contribute to the age‐associated decline in cardiac performance are poorly understood. Herein, we identify the involvement of sodium/glucose co‐transporter gene (SGLT2) in disrupted cellular Ca2+‐homeostasis, and mitochondrial dysfunction in age‐associated cardiac dysfunction. In contrast to younger rats (6‐month of age), older rats (24‐month of age) exhibited severe cardiac ultrastructural defects, including deformed, fragmented mitochondria with high electron densities. Cardiomyocytes isolated from aged rats demonstrated increased reactive oxygen species (ROS), loss of mitochondrial membrane potential and altered mitochondrial dynamics, compared with younger controls. Moreover, mitochondrial defects were accompanied by mitochondrial and cytosolic Ca2+ ([Ca2+]i) overload, indicative of disrupted cellular Ca2+‐homeostasis. Interestingly, increased [Ca2+]i coincided with decreased phosphorylation of phospholamban (PLB) and contractility. Aged‐cardiomyocytes also displayed high Na+/Ca2+‐exchanger (NCX) activity and blood glucose levels compared with young‐controls. Interestingly, the protein level of SGLT2 was dramatically increased in the aged cardiomyocytes. Moreover, SGLT2 inhibition was sufficient to restore age‐associated defects in [Ca2+]i‐homeostasis, PLB phosphorylation, NCX activity and mitochondrial Ca2+‐loading. Hence, the present data suggest that deregulated SGLT2 during ageing disrupts mitochondrial function and cardiac contractility through a mechanism that impinges upon [Ca2+]i‐homeostasis. Our studies support the notion that interventions that modulate SGLT2‐activity can provide benefits in maintaining [Ca2+]i and cardiac function with advanced age.

Targeting the forkhead box protein P1 pathway as a novel therapeutic approach for cardiovascular diseases.

Cardiovascular disease (CVD) is the leading cause of death worldwide and encompasses diverse diseases of the vasculature, myocardium, cardiac electrical circuit, and cardiac development. Forkhead box protein P1 (Foxp1) is a large multi-domain transcriptional regulator belonging to the Fox family with winged helix DNA-binding protein, which plays critical roles in cardiovascular homeostasis and disorders. The broad distribution of Foxp1 and alternative splicing isoforms implicate its distinct functions in diverse cardiac and vascular cells and tissue types. Foxp1 is essential for diverse biological processes and has been shown to regulate cellular proliferation, apoptosis, oxidative stress, fibrosis, angiogenesis, cardiovascular remodeling, and dysfunction. Notably, both loss-of-function and gain-of-function approaches have defined critical roles of Foxp1 in CVD. Genetic deletion of Foxp1 results in pathological cardiac remodeling, exacerbation of atherosclerotic lesion formation, prolonged occlusive thrombus formation, severe cardiac defects, and embryo death. In contrast, activation of Foxp1 performs a wide range of physiological effects, including cell growth, hypertrophy, differentiation, angiogenesis, and cardiac development. More importantly, Foxp1 exerts anti-inflammatory and anti-atherosclerotic effects in controlling coronary thrombus formation and myocardial infarction (MI). Thus, targeting for Foxp1 signaling has emerged as a pre-warning biomarker and a novel therapeutic approach against progression of CVD, and an increased understanding of cardiovascular actions of the Foxp1 signaling will help to develop effective interventions. In this review, we focus on the diverse actions and underlying mechanisms of Foxp1 highlighting its roles in CVD, including heart failure, MI, atherosclerosis, congenital heart defects, and atrial fibrillation.

Atypical ALPK2 kinase is not essential for cardiac development and function.

Protein kinases play an integral role in cardiac development, function, and disease. Recent experimental and clinical data have implied that protein kinases belonging to a family of atypical α-protein kinases, including α-protein kinase 2 (ALPK2), are important for regulating cardiac development and maintaining function via regulation of WNT signaling. A recent study in zebrafish reported that loss of ALPK2 leads to severe cardiac defects; however, the relevance of ALPK2 has not been studied in a mammalian animal model. To assess the role of ALPK2 in the mammalian heart, we generated two independent global Alpk2-knockout (Alpk2-gKO) mouse lines, using CRISPR/Cas9 technology. We performed physiological and biochemical analyses of Alpk2-gKO mice to determine the functional, morphological, and molecular consequences of Alpk2 deletion at the organismal level. We found that Alpk2-gKO mice exhibited normal cardiac function and morphology up to one year of age. Moreover, we did not observe altered WNT signaling in neonatal Alpk2-gKO mouse hearts. In conclusion, Alpk2 is dispensable for cardiac development and function in the murine model. Our results suggest that Alpk2 is a rapidly evolving gene that lost its essential cardiac functions in mammals.NEW & NOTEWORTHY Several studies indicated the importance of ALPK2 for cardiac function and development. A recent study in zebrafish report that loss of ALPK2 leads to severe cardiac defects. In contrast, murine Alpk2-gKO models developed in this work display no overt cardiac phenotype. Our results suggest ALPK2, as a rapidly evolving gene, lost its essential cardiac functions in mammals.

Mortality burden in patients born with Ebstein's anomaly: a 40-year nationwide cohort study.

Survival rates for unoperated patients with Ebstein's anomaly (EA) are unknown. We estimated overall long-term mortality in operated and unoperated EA patients, compared with the general population in Sweden. Using national medical registries, Swedish individuals born 1970-93 and diagnosed with EA between 1970 and 2011 were included. The hazard ratio for overall mortality for EA patients (n = 216) vs. the matched comparison cohort (n = 2160) was 43.7 [95% confidence interval (CI): 24.8-82.5]. Mortality risk for EA patients (vs. controls) decreased as birth period progressed, with hazard ratios declining from 63.6 (95% CI: 26.3-191.8) for those born in the 1970s to 34.4 (95% CI: 15.8-83.1) for those born in the 1980s and 20.2 (95% CI: 1.6-632.5) for those born at the beginning of 1990s. The overall mortality hazard ratios for unoperated and operated patients with EA (vs. controls) were 30.2 (95% CI: 13.8-73.3) and 63.7 (95% CI: 28.1-172.5), respectively. The risk of mortality among unoperated EA patients (vs. controls) declined with progressing birth period, with hazard ratios declining from 58.4 (95% CI: 15.1-415.2) in the 1970s to 22.9 (95% CI: 8.0-75.3) in the 1980s and 10.2 (95% CI: 0.3-395.9) in the 1990s. Overall all-cause mortality for patients with EA declined dramatically from 64 times to 20 times that of controls without EA, from the 1970s to the early 1990s. Unoperated patients with EA had better survival than did operated patients, possibly reflecting the higher severity of disease or more severe associated cardiac defects in patients undergoing surgery.