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Pulmonary atresia (PA) is a severe cyanotic congenital heart disease. Although some genetic mutations have been described to be associated with PA, the knowledge of pathogenesis is insufficient. The aim of this research was to use whole-exome sequencing (WES) to determine novel rare genetic variants in PA patients. We performed WES in 33 patients (27 patient–parent trios and 6 single probands) and 300 healthy control individuals. By applying an enhanced analytical framework to incorporate de novo and case–control rare variation, we identified 176 risk genes (100 de novo variants and 87 rare variants). Protein‒protein interaction (PPI) analysis and Genotype-Tissue Expression analysis revealed that 35 putative candidate genes had PPIs with known PA genes with high expression in the human heart. Expression quantitative trait loci analysis revealed that 27 genes that were identified as novel PA genes that could be affected by the surrounding single nucleotide polymorphism were screened. Furthermore, we screened rare damaging variants with a threshold of minor allele frequency at 0.5% in the ExAC_EAS and GnomAD_exome_EAS databases, and the deleteriousness was predicted by bioinformatics tools. For the first time, 18 rare variants in 11 new candidate genes have been identified that may play a role in the pathogenesis of PA. Our research provides new insights into the pathogenesis of PA and helps to identify the critical genes for PA.

BackgroundThe capacity to distinguish hypertrophic cardiomyopathy (HCM) from hypertensive left ventricular hypertrophy (H-LVH) based on morphological features obtained by conventional echocardiography is limited. We investigated the global myocardial work of the left ventricle in two types of hypertrophies using the non-invasive myocardial work index (NMWI).MethodsConventional echocardiography was performed on 107 subjects with preserved left ventricular ejection fraction (LVEF ≥ 50%), who comprised patients with HCM (n = 40), H-LVH (n = 35), and healthy people with normal blood pressure and left ventricular structure (n = 32). Except for the conventional echocardiographic parameters, the left ventricular myocardial work parameters based on pressure-strain loops, including global myocardial work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE), were evaluated in three groups. Multivariate discriminant analysis and receiver operating characteristic (ROC) curve were used to evaluate the incremental value of NMWI for distinguishing HCM from H-LVH.ResultsCompared to the control group, GWI and GCW were significantly lower in HCM patients (P < 0.05), whereas GWI was significantly higher in H-LVH patients. GWW was higher and GWE was significantly decreased in both HCM and H-LVH patients than in the control group (P < 0.05). Multivariate discriminant analysis and ROC curve revealed that the inter-ventricular septum thickness (IVST)/left ventricular posterior wall thickness (LVPWT) and GCW were each able to distinguish HCM from H-LVH. The combination of IVST/LVPWT and GCW discriminated HCM and H-LVH with a higher predictive accuracy of 94.7%.ConclusionNMWI may provide additional information in evaluating the myocardial function in patients with HCM and H-LVH. Myocardial work combined with conventional echocardiography could improve the clinical diagnostic accuracy of distinguishing HCM and H-LVH.

Coronary artery fistula (CAF) is a rare cardiac anomaly. Here, we diagnosed a right coronary artery-right atrium fistula with giant coronary artery aneurysm (CAA) via fetal echocardiography at 35 weeks' gestation. An urgent caesarean delivery was performed at 36 weeks' gestation because CAA caused mitral obstruction, and fetal atrial flutter was present. Following delivery, we performed aneurysm ligation because the new-born developed atrial tachycardia. The intraoperative findings confirmed the sonographic findings. To the best of our knowledge, prenatal ultrasound diagnosis of CAF and giant CAA has not been reported in the literature. We focus on the ultrasonic characteristics and differential diagnosis in this literature.

BackgroudNoninvasive myocardial work, estimated by left ventricular (LV) pressure-strain loop (PSL), has been introduced for assessing LV myocardial performance. Based on both blood pressure and speckle-tracking derived strain data, noninvasive myocardial work is considered to be less load-dependent than global longitudinal strain (GLS). In some conditions, such as hypertension or aortic coarctation, the increased afterload will affect strain measurements, and myocardial work can serve as a more robust metric.ObjectiveWe prospectively recruited healthy children to explore the relationship between myocardial work indices and body size parameters, and to determine the reference values of noninvasive myocardial work indices in healthy children.Methods183 healthy children (aged 1–18 years, males: 52.5%) were enrolled in the study. Global work index (GWI), global constructive work (GCW), global wasted work (GWW), global work efficiency (GWE), were assessed by LVPSL and compared according to age and sex.ResultsThe mean for GWI was 1,448.7 ± 265.0 mm Hg%, 1,859.8 ± 290.7 mm Hg% for GCW, and the median (interquartile range) for GWW was 54.0 (33.0–82.0) mm Hg% and 97.0 (95.0–99.0) % for GWE. male had greater GWI and GCW) than female (1,572.5 ± 250.2 mm Hg% vs. 1,312.2 ± 208.7 mm Hg% and 1,944.3 ± 299.2 mm Hg% vs. 1,766.6 ± 251.5 mm Hg%, respectively, all P < 0.001). GWI and GCW were significantly correlated with baseline parameters, including age, height, weight, BSA, body mass index, heart rate, and blood pressure. After indexed to BSA, GWI (BSA), GCW (BSA) remained significantly negatively correlated with age (P < 0.001).Conclusionswe proposed the normal reference values and regression equations for GWI and GCW based on age and BSA in healthy children. This might provide a basis of reference for the evaluation of cardiac function in children with cardiopulmonary disease.

Background Cardiac damage is the leading cause of death in uremic patients. This study aimed to evaluate the application of non-invasive myocardial work index (NIMWI) by echocardiography in assessing the left ventricular (LV) systolic function in uremic patients. Methods Twenty-six uremic patients and 27 age- and sex-matched healthy volunteers were enrolled in the study. Except for the conventional echocardiographic parameters, the LV myocardial work (MW) parameters including GWI (myocardial global work index), GCW (global constructive work), GWW (global wasted work), and GWE (global work efficiency) were calculated in study participants. Differences in MW parameters between the uremic and normal groups were compared by independent-sample t-test. Receiver operating characteristic (ROC) curves were constructed for MW parameters to detect abnormal LV systolic function in uremic patients. Results Compared with the normal group, GWW was significantly increased and GWE decreased in the uremic group (P Conclusions NIMWI may be applied to assess the global MW of uremic patients. The presence of reduced GWE can help identify impaired left ventricular myocardial function in uremic patients with preserved LV ejection fraction with a high sensitivity and specificity.

Objectives: To analyze the association between global myocardial work indices evaluated by non-invasive left ventricular (LV) pressure-strain loop (PSL) and LV myocardial fibrosis in patients with dilated cardiomyopathy (DCM).Methods: A total of 57 patients with DCM were included in this prospective study. Global work index (GWI), global constructive work (GCW), global wasted work (GWW), global work efficiency (GWE) and global longitudinal strain (GLS) were measured using LVPSL. LV volumes and LV ejection fraction (LVEF) were evaluated using cardiac magnetic resonance imaging (CMRI), LV myocardial fibrosis was estimated at CMRI by qualitative assessment of late gadolinium enhancement (LGE). According to the CMRI, the studied population was divided into two groups, namely: patients without LGE (LGE-) and patients with LGE (LGE+).Results: The LGE+ group presented with increased age, LV end systolic volume (LVESV) index and reduced GWI, GCW, GWE, GLS, CMRI-derived LVEF (LVEFCMRI), the differences between the two groups were statistically significant (P < 0.05). After correcting for age and LVESV index, LVEFCMRI, GLS, GWI, GCW, and GWE retained independent associations with LV myocardial fibrosis. According to receiver operating characteristics (ROC) analysis, LVEFCMRI, and GCW showed larger AUC and higher accuracy, sensitivity, and specificity than GLS, the accuracy of predicting LV myocardial fibrosis ranged from high to low as: LVEFCMRI, GCW, GWE, GWI, and GLS.Conclusions: LVEFCMRI, GWI, GCW, GWE, and GLS remained significant predictors of LV myocardial fibrosis. LVEFCMRI, and GCW appeared to better predict LV myocardial fibrosis compared with GLS.

Tetralogy of Fallot (TOF) is still the most common and complicated cyanotic congenital heart defect of all congenital heart diseases with a 10% incidence. Surgery repair is often necessary in infancy. The etiology of TOF is complex and genetic and epigenetic mechanisms such as chromosomal abnormalities, gene mutations, nucleic acid modifications, non-coding RNA, and circular RNA(circRNA) play an important role in its occurrence. RNA not only plays an auxiliary role of genetic information carrier, but also plays a more important role in various regulatory functions. There are few studies on the action mechanism of non-coding RNA. Aim to gain more in-depth knowledge of TOF, we collected tissue samples of the right ventricular outflow tract of 5 TOF children with no other intracardiac and extracardiac malformations and 5 normal fetuses. We systematically analyzed the specific long non-coding RNA (lncRNA), microRNA(miRNA), circRNA and messenger RNA(mRNA) profiles of TOF. To our knowledge, there are no reports of genome-wide study of transcriptome in TOF and we first obtained meaningful differentially expressed lncRNAs, miRNAs, circle RNA and mRNAs.

// Lin Liu 1, * , Hong-Dan Wang 2, * , Cun-Ying Cui 1 , Yun-Yun Qin 1 , Tai-Bing Fan 3 , Bang-Tian Peng 3 , Lian-Zhong Zhang 1 and Cheng-Zeng Wang 4 1 Department of Cardiovascular Ultrasound, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou 450003, China 2 Institute of Medical Genetics, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou 450003, China 3 Children’s Heart Center, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou 450003, China 4 Department of Ultrasound, The Affiliated Cancer Hospital, Zhengzhou University, Zhengzhou 450008, China * These authors have contributed equally to this work Correspondence to: Lin Liu, email: liulin_819@126.com Keywords: tetralogy of Fallot; congenital heart disease; whole exome sequencing Received: April 05, 2017 Accepted: September 05, 2017 Published: October 31, 2017 ABSTRACT Background: Tetralogy of Fallot is the most common cyanotic congenital heart disease. However, its pathogenesis remains to be clarified. The purpose of this study was to identify the genetic variants in Tetralogy of Fallot by whole exome sequencing. Methods: Whole exome sequencing was performed among eight small families with Tetralogy of Fallot. Differential single nucleotide polymorphisms and small InDels were found by alignment within families and between families and then were verified by Sanger sequencing. Tetralogy of Fallot-related genes were determined by analysis using Gene Ontology /pathway, Online Mendelian Inheritance in Man, PubMed and other databases. Results: A total of sixteen differential single nucleotide polymorphisms loci and eight differential small InDels were discovered. The sixteen differential single nucleotide polymorphisms loci were located on Chr 1, 2, 4, 5, 11, 12, 15, 22 and X. Among the sixteen single nucleotide polymorphisms loci, six has not been reported. The eight differential small InDels were located on Chr 2, 4, 9, 12, 17, 19 and X, whereas of the eight differential small InDels, two has not been reported. Analysis using Gene Ontology /pathway, Online Mendelian Inheritance in Man, PubMed and other databases revealed that PEX5 , NACA , ATXN2 , CELA1 , PCDHB4 and CTBP1 were associated with Tetralogy of Fallot. Conclusions: Our findings identify PEX5 , NACA , ATXN2 , CELA1 , PCDHB4 and CTBP1 mutations as underlying genetic causes of isolated tetralogy of Fallot.

The aim of our prospective pilot study was to explore the distribution characteristics of myocardial work (MW) of patients with dilated cardiomyopathy (DCM) and their clinical value in evaluation of therapeutic effects. Thirty patients with DCM were enrolled in the case group, and 30 healthy patients were randomly allocated to the control group. Global myocardial work (GMW) and regional myocardial work (RMW) of the control and case groups before and after therapy were evaluated by using left ventricular pressure-strain loops and then compared. We found significant differences in GMW and RMW between the control and case groups (p < 0.05). Compared with before therapy, the global work index and 6-min walking distance increased, but LV ejection fraction and global longitudinal strain did not significantly change after therapy. GMW was significantly correlated with LV ejection fraction and global longitudinal strain (p < 0.01). Bland-Altman plot analysis revealed that GMW values were consistent between and within the groups. The results suggest that LV MW values were diffusely impaired in patients with DCM and that the global work index may be used as an indicator in evaluation of therapeutic effects.

Objective The objective of this study was to evaluate the feasibility of online real time three-dimensional transesophageal echocardiography (RT3DTEE) in the measurement of left atrial appendage (LAA) orifice size. We also analyzed the correlation between LAA ejection fraction (EF) and its peak empty velocity (PEV). Methods There were 91 subjects enrolled in this study, with 46 patients with AF and 45 individuals with sinus rhythm (SR). RT3DTEE was performed by four methods including iSlice and iCrop online and QLAB software 3DQ and GI-3DQ off-line which were used to measure LAA orifice area, long diameter, short diameter, depth in the largest LAA, and number of LAA lobes. These LAA parameters achieved by the four methods were compared, respectively. GI-3DQ off-line was used to measure LAA end-diastolic and end-systolic volumes to calculate EF of LAA. Two-dimensional (2D) TEE was applied to measure PEV of LAA. The correlation between EF and PEV was analyzed. Results There were no significant differences in all LAA parameters between any two RT3DTEE methods (All P > .05). There was a significant and positive correlation between PEV and EF (r = .423, P = .000). There were statistical differences in LAA EF and PEV between patients with AF and SR individuals (0.38 ± 0.12 vs 0.61 ± 0.07, 35.7 ± 12.1 vs 49.5 ± 10.0 cm/s, P = .000). Conclusion Using online RT3DTEE for measuring LAA orifice size is feasible, and online RT3DTEE is more convenient than offline RT3DTEE. EF is positively correlated with PEV. LAA function is significantly decreased in patients with AF.

Objectives To explore the application values of layer-specific strain technology in the assessment of left ventricular (LV) systolic function and synchronicity before and after coronary artery bypass graft (CABG) in patients with coronary artery disease (CAD). Methods Thirty-three CAD patients scheduled for CABG were recruited, along with 35 controls without cardiovascular disease. The images of apical four, two and three chamber views of LV were collected before CABG and 1 week, 1 month and 3 months after CABG. The layer-specific longitudinal peak strains, time to peak and peak strain dispersion (PSD) were determined for 17 segments of LV using Echo PAC workstation software and Q-analysis software. The differences of these parameters were compared between groups. Results The absolute values of layer-specific longitudinal peak strains at subendocardium, middle layer and subepicardium, respectively represented by GLPSendo, GLPSmid and GLPSepi, decreased significantly (P 0.05) and absolute values of GLPSendo, GLPSmid and GLPSepi 3 months after CABG (P>0.05). At 1 month and 3 months, PSD decreased significantly (P 0.05). Conclusions Layer-specific strain technology provides a quantitative evaluation approach for LV systolic function and synchronicity before and after CABG in CAD patients. As a novel parameter in assessing LV systolic synchronicity, PSD is worthy of clinical popularization.

Tetralogy of Fallot (ToF) can be challenging for clinicians to both diagnose and treat, given the multiple heart defects that are by definition associated with the illness. This study investigates the value of real-time three- dimensional echocardiography (RT-3DE) in evaluating the pre-and postoperative right ventricular systolic function of patients with tetralogy of Fallot. A total of 41 ToF patients were divided into two groups: the child group (CG) and the adult group (AG) according to age. The right ventricular end-diastolic volume (RVEDV), right ventricular end-systolic volume (RVESV), and the right ventricular ejection fraction (RVEF) of ToF patients were measured before surgery, 7 days, and 3 months after the surgery. The correlation between the preoperative Nakata index and RVEF was then analyzed. Compared with the RVEDV and RVESV prior to surgery, those of the postoperative 7-day and 3-month were not statistically significant (p0.05). However, RVEF decreased, and the difference was statistically significant (p0.05). The differences in RVEDV, RVESV, and RVEF between postoperative 3-month and 7-day were not significant (p0.05). Compared with the pre-and postoperative RVEDV and RVESV of CG, those of AG increased. However, RVEF decreased, and the differences were statistically significant (p0.05). Our study indicated that the correlation between preoperative Nakata index and RVEF was good. Ultimately, we did confirm that RT-3DE can quantitatively evaluate the right ventricular volume and systolic function of ToF patients, thereby providing clinical significance in determining postoperative efficacy and prognosis evaluation.Echocardiography; Right; Tetralogy of Fallot; Three-dimensional; Ventricular function.

Background Little information is available regarding the penetrance of 1q21.1 copy number variants (CNVs). In the present study, we explored the clinical significance of 1q21.1 microdeletion or microduplication. Methods In four families, chromosome karyotype was analyzed using G‐banding karyotype analysis technology. CNVs were detected using array‐comparative genomic hybridization (aCGH) and then a quantitative polymerase chain reaction (qPCR) was used to validate candidate CNVs. Sequence signature in the breakpoint region was analyzed using University of California Santa Cruz (UCSC) databases. Results Except for karyotype 45, XX, der (13, 14) (q10, q10) in the mother (I2) of family 2, the karyotype was normal in all other members of the four families. In the mother (I2) and fetus (II2) of family 1, in newborn (II1) of family 2 and in fetus (II1) of family 3, there was 1.22‐Mb heterozygous microdeletion in the chromosome 1q21.1q21.2 region. The child (II1) of family 4 had a 1.46‐Mb heterozygous microduplication in the chromosome 1q21.1q21.2 region. The results of the qPCR were consistent with that of aCGH. There was large number of low copy repeats (LCRs) in the breakpoint region found by analysis of the UCSC database, and multiple LCRs were matched with sequences in the chromosome 1 short‐arm region. Conclusions 1q21.1 microdeletion and microduplication exhibit a variety of clinical manifestations and the specificity of their clinical features is not high. The penetrance of the distal 1q21.1 microdeletion may be affected by other factors in the present study. In summary, we report the discovery of a new distal 1q21.1 microduplication, which enriches the CNV spectrum in the 1q21.1 region and is conducive to prenatal genetic counseling.