Association of PLXND1 with a novel subtype of anomalous pulmonary venous return.

Anomalous pulmonary venous return (APVR) is a potentially lethal congenital heart disease. Elucidating the genetic etiology is crucial for understanding its pathogenesis and improving clinical practice, whereas its genetic basis remains largely unknown because of complex genetic etiology. We thus performed whole-exome sequencing for 144 APVR patients and 1636 healthy controls and report a comprehensive atlas of APVR-related rare genetic variants. Novel singleton, loss-of-function and deleterious missense variants (DVars) were enriched in patients, particularly for genes highly expressed in the developing human heart at the critical time point for pulmonary veins draining into the left atrium. Notably, PLXND1, encoding a receptor for semaphorins, represents a strong candidate gene of APVR (adjusted P = 1.1e-03, odds ratio: 10.9-69.3), accounting for 4.17% of APVR. We further validated this finding in an independent cohort consisting of 82 case-control pairs. In these two cohorts, eight DVars were identified in different patients, which convergently disrupt the GTPase-activating protein-related domain of PLXND1. All variant carriers displayed strikingly similar clinical features, in that all anomalous drainage of pulmonary vein(s) occurred on the right side and incorrectly connected to the right atrium, which may represent a novel subtype of APVR for molecular diagnosis. Studies in Plxnd1 knockout mice further revealed the effects of PLXND1 deficiency on severe heart and lung defects and cellular abnormalities related to APVR such as abnormal migration and vascular formation of vascular endothelial cells. These findings indicate the important role of PLXND1 in APVR pathogenesis, providing novel insights into the genetic etiology and molecular subtyping for APVR.

Incremental value of myocardial global longitudinal strain in predicting major adverse cardiac events among patients with hypertrophic cardiomyopathy.

OBJECTIVES: Endocardial global longitudinal strain (endo-GLS) measured with echocardiography (echo) has been demonstrated to be associated with myocardial fibrosis (MF) and is a prognostic predictor in patients with hypertrophic cardiomyopathy (HCM). Late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) imaging showed that MF is primarily located in the myocardial layer of the extremely hypertrophic septal or ventricular wall. We hypothesized that GLS of the myocardial layer (myo-GLS) is more strongly correlated with the extent of LGE (%LGE) and is a more powerful prognostic factor than endo-GLS. METHODS: A total of 177 inpatients (54.0 [IQR: 43.0, 64.0] years, female 37.3%) with HCM were retrospectively included from May 2019 to April 2021. Among them, 162 patients underwent echocardiographic examination and contrast-enhanced CMR within 7 days. Myo-GLS and %LGE were blindly assessed in a core laboratory. All the patients were followed after they were discharged. RESULTS: During a mean follow-up of 33.77 [IQR 30.05, 35.40] months, 14 participants (7.91%) experienced major adverse cardiac events (MACE). The MACE (+) group showed lower absolute endo-GLS and myo-GLS than the MACE (-) group. Myo-GLS was more associated with %LGE (r = -.68, P < .001) than endo-GLS (r = -.64, P < .001). Cox multivariable analysis indicated that absolute myo-GLS was independently associated with MACE (adjusted hazard ratio = .75, P < .05). Myo-GLS was better than endo-GLS at detecting MACE (+) patients (-8.64%, AUC .939 vs. - 16.375%, AUC .898, P < .05). CONCLUSIONS: Myo-GLS is a stronger predictor of MACE than endo-GLS in patients with HCM and is highly correlated with %LGE.

Exome-Based Case-Control Analysis Highlights the Pathogenic Role of Ciliary Genes in Transposition of the Great Arteries.

RATIONALE: Transposition of the great arteries (TGA) is one of the most severe types of congenital heart diseases. Understanding the clinical characteristics and pathogenesis of TGA is, therefore, urgently needed for patient management of this severe disease. However, the clinical characteristics and genetic cause underlying TGA remain largely unexplored. OBJECTIVE: We sought to systematically examine the clinical characteristics and genetic cause for isolated nonsyndromic TGA. METHODS AND RESULTS: We recruited 249 patients with TGA (66 family trios) and performed whole-exome sequencing. The incidence of patent ductus arteriosus in dextro-TGA (52.7%) and dextrocardia/mesocardia in congenitally corrected TGA (32.8%) were significantly higher than that in other subtypes. A high prevalence of bicuspid pulmonic valve (9.6%) was observed in patients with TGA. Similar results were observed in a replication group of TGA (n=132). Through a series of bioinformatics filtering steps, we obtained 82 candidate genes harboring potentially damaging de novo, loss of function, compound heterozygous, or X-linked recessive variants. Established congenital heart disease-causing genes, such as FOXH1, were found among the list of candidate genes. A total of 19 ciliary genes harboring rare potentially damaging variants were also found; for example, DYNC2LI1 with a de novo putatively damaging variant. The enrichment of ciliary genes supports the roles of cilia in the pathogenesis of TGA. In total, 33% of the TGA probands had >1 candidate gene hit by putatively deleterious variants, suggesting that a portion of the TGA cases were probably affected by oligogenic or polygenic inheritance. CONCLUSIONS: The findings of clinical characteristic analyses have important implications for TGA patient stratification. The results of genetic analyses highlight the pathogenic role of ciliary genes and a complex genetic architecture underlying TGA.

Doubly committed subarterial ventricular septal defect closure through tricuspid approach: a clinical analysis.

BACKGROUND: The research was to introduce the experience of doubly committed subarterial ventricular septal defect (DCVSD) repaired through tricuspid approach. METHODS: From January, 2015 to September, 2019, 86 consecutive DCVSD paediatrics underwent repair via right subaxillary vertical incision (RAVI) through tricuspid approach. Perioperative and follow-up data were collected. RESULTS: The age and weight at operation were 28.1 ± 18.5 (range: 7-101) months and 12.2 ± 4.2 (6-26.5) kg. There were two patients combined with discrete subaortic membrane, two patients with patent ductus arteriosus, one patient with atrial septal defect, and two patients with abnormal muscle bundle in right ventricular outflow tract. The mean size of ventricular septal defect was 7.0 ± 2.4 (3-13) mm. The defect was repaired with a piece of Dacron patch in 68 patients or directly with 1-2 pledgetted polypropylene sutures in 18 patients. The cardiopulmonary bypass time and aortic cross-clamp time were 46.2 ± 13.3 (23-101) minutes and 29.2 ± 11.5 (12-84) minutes. After 3.1 ± 2.4 (0-14) hours' ventilator assist and 23.2 ± 32.1 (0-264) hours' ICU stay, all patients were discharged safely. At the latest follow-up (27.9 ± 14.6 months), echocardiography showed trivial residual shunt in two patients. There was no malignant arrhythmia occurred and there was no chest deformity or asymmetrical development of the breast was found. CONCLUSIONS: DCVSD repaired via right subaxillary vertical incision through tricuspid approach was safe and feasible, providing a feasible alternative to median sternotomy, and it can be performed with favourable cosmetic results.

Ultrasound-Guided Percutaneous Balloon Aortic Valvuloplasty for Aortic Stenosis.

Percutaneous balloon aortic valvuloplasty (PBAV), which is used to treat symptomatic aortic stenosis, requires ionizing radiation and contrast agent for imaging guidance. The aim of the study is to evaluate the feasibility and effectiveness of ultrasound-guided PBAV in patients with aortic stenosis. This case series included 30 patients (14 males; mean age, 61.5 ± 4.5 years) with moderate/severe aortic stenosis treated with ultrasound-guided PBAV at the Ultrasound Department, Fuwai Hospital, Beijing, China, between January 2016 and July 2019. Cardiac function (New York Heart Association grade) was assessed before PBAV and 1 month after the procedure. Aortic peak jet velocity, aortic valve orifice area (AVA), mean transvalvular pressure gradient (MTPG), left ventricular end-diastolic diameter (LVDD), left ventricular ejection fraction (LVEF), and left ventricular end-systolic diameter (LVESD) were determined before and immediately after PBAV using Doppler echocardiography. Preprocedural cardiac function was grade I in 3 cases, grade II in 9 cases, grade III in 10 cases, and grade IV in 8 cases. Postprocedural cardiac function was grade I in 22 cases, grade II in 4 cases, and grade III in 4 cases, suggesting that cardiac function was improved by PBAV. Ultrasound-guided PBAV resulted in significant improvements (P < 0.05) in aortic peak jet velocity (3.68 ± 0.811 m/s vs. 4.79 ± 0.63 m/s), MTPG (33.77 ± 13.85 mmHg vs. 54.54 ± 13.81 mmHg), AVA (1.96 ± 0.25 cm2 vs. 0.98 ± 0.12 cm2), LVEDD (51.90 ± 3.21 mm vs. 65.60 ± 6.81 mm), LVEF (63.46 ± 11.29% vs. 56.31 ± 11.04%), and LVESD (35.50 2.62 mm vs. 45.20 ± 2.42 mm). Ultrasound-guided PBAV is feasible and achieves good short-term effects in patients with aortic stenosis.

Left atrial reservoir strain combined with E/E' as a better single measure to predict elevated LV filling pressures in patients with coronary artery disease.

BACKGROUND: The 2016 guidelines for left ventricular diastolic dysfunction diagnosis has been simplified from previous versions; however, multiparametric diagnosis approach still exists indeterminate left ventricular diastolic dysfunction category. Left atrial (LA) strain was recently found useful to predict elevated left ventricular (LV) filling pressures noninvasively. This study aimed to (1) analyze the diagnostic value of LA strain for noninvasive assessment of LV filling pressures in patients with stable coronary artery disease (CAD) with preserved LV ejection fraction (LVEF), using invasive hemodynamic assessment as the gold standard, and (2) explore whether LA strain combined with conventional diastolic parameters could detect elevated LV filling pressures alone. METHODS: Sixty-four patients with stable CAD having LVEF > 50% and 30 healthy controls were enrolled. Two-dimensional speckle-tracking echocardiography was used to measure LA strain during the reservoir (LASr), conduit, and contraction phases. LV end-diastolic pressure (LVEDP), as a surrogate for LV filling pressures, was invasively obtained by left heart catheterization. Logistic regression was used to calculate the odds ratio to predict LV filling pressures. Pearson's correlation was used to analyze associations between echocardiographic parameters and LVEDP. The area under the receiver-operating characteristic curve was calculated to determine the capability of the echocardiographic parameters to detect elevated LVEDP. Inter-technique agreement was analyzed by contingency tables and tested by kappa statistics. RESULTS: LASr and the ratio of early-diastolic transmitral flow velocity (E) to tissue Doppler early-diastolic septal mitral annular velocity (E/E'septal) significantly predicted elevated LV filling pressures. LASr was combined with E/E'septal to generate a novel parameter (LASr/E/E'septal). LASr/E/E'septal had the best predictive ability of elevated LV filling pressures. LVEDP was negatively correlated with LASr and LASr/E/E'septal but positively correlated with E/E'septal. The area under the receiver-operating characteristic curve of LASr/E/E'septal was higher than that of LASr alone (0.83 vs. 0.75), better than all conventional LV diastolic parameters. Inter-technique agreement analysis showed that LASr/E/E'septal had good agreement with the invasive LVEDP measurement, better than the 2016 guideline (kappa = 0.63 vs. 0.25). CONCLUSIONS: LASr provided additive diagnostic value for the noninvasive assessment of LV filling pressures. LASr/E/E'septal had the potential to be a better single noninvasive index to predict elevated LV filling pressures in patients with stable CAD and preserved LVEF.

Evaluation of the Left Ventricular Hemodynamic Status of Double-Root Translocation Patients Through Vector Flow Mapping.

The double-root translocation (DRT) procedure is considered as a new choice for surgical management of complex congenital heart disease. Our study aims to investigate the left ventricular hemodynamic status after DRT by energy loss (EL), involving 42 patients who underwent DRT as well as 42 healthy volunteers as controls. The EL of left ventricle (LV) during different periods (rapid filling-RF, atrial contraction-AC, isovolumic contraction-IVC, rapid ejection-RE) of the same cardiac cycle were obtained and analyzed. Compared to the controls, global LV and apical three chamber-EL at AC and IVC periods in DRT group were higher (p < 0.05), and EL at RE period of DRT group was moderately lower. In the correlation analysis, the global EL at the RF was correlated with E wave (r = 0.47, p = 0.03), E/e' (r = 0.50, p = 0.02), BSA (r = - 0.54, p = 0.01), and age (r = - 0.67, p < 0.001). AC and RE- global EL were significantly correlated with E/e' (r = 0.49, r = 0.59, p < 0.05). There was a strong positive correlation between E/e' and global EL at the IVC (r = 0.62, p = 0.003) and a moderate negative correlation with age (r = - 0.44, p = 0.04). The present study confirms that EL is a feasible and reproducible indicator for quantitatively evaluating LV hemodynamic status in patients who underwent DRT and reveals that DRT can lead to approximatively normal long-term hemodynamic performance of LV.

Modified Single Repair Technique for Complete Atrioventricular Septal Defect: A Propensity Score Matching Analysis.

There were controversies about the priority of modified single patch (MSP) technique compared with two-patch (TP) technique for patients with complete atrioventricular septal defect (CAVSD). From 2002 to 2013, patients who diagnosed as balanced CAVSD in our institution were retrospectively included. Patients with unbalanced ventricles or associated anomalies were excluded. The primary endpoint was all-cause mortality and the secondary endpoint consist of left atrioventricular dysfunction or left atrioventricular outflow tract obstruction (LVOTO). A total of 74 patients underwent MSP repair and 102 patients underwent TP repair. After 1:1 propensity matching, there were 46 Rastelli type A CAVSD patients in each group. Patients in MSP group had shorter cardiopulmonary bypass time [median (interquartile range) 73.5 (65.5-95.0) versus 105.0 (88.8-130.0) min, P < 0.001] and aortic cross-clamp time [105.5 (90.0-128.0) versus 143.0 (122.0-184.0) min, P < 0.001]. In total, the primary endpoint occurred in 12 patients, including 2/46 (4.3%) in MSP group and 10/46 (21.7%) in TP group. That 1-year, 3-year, 5-year survival rate can be calculated as 95.6%, 95.6%, 95.6% in MSP group and 92.6%, 80.4%, 78.2% in TP group, P = 0.015. No significant statistical difference found for the secondary endpoints that 7/46 (15.2%) patients occurred moderate or severe LAVVR in MSP group versus 11/46 (23.9%) patients in TP group, P = 0.293. No LVOTO occurred in both groups. Besides the simplicity of technique, MSP technique may be safer.

Tricuspid valvuloplasty for isolated tricuspid regurgitation in children.

BACKGROUND: Isolated congenital tricuspid regurgitation other than Ebstein's anomaly was rare especially for children. The objective of this study was to investigate the clinical characteristics and to assess the results of tricuspid valvuloplasty for children with isolated tricuspid regurgitation. METHODS: From January 2010 to June 2019, 10 consecutive patients with isolated tricuspid regurgitation who were unresponsive to drug therapy underwent tricuspid valvuloplasty in our hospital. Patients' clinical data were analysed retrospectively. RESULTS: Mean age at operation was 48.5 ± 31.0 (range: 9-106) months and mean weight at operation was 16.1 ± 6.9 (range: 8.6-33.0) kg. All patients presented severe isolated tricuspid regurgitation. According to pathological lesions, the main causes accounted for chordae tendinea rupture (3/10), leaflet cleft (2/10), mal-connected chordal tendinea to leaflets (2/10), elongated chordae (1/10) and chordae absent (1/10), and severe anterior leaflet dysplasia (1/10). Individualised tricuspid valvuloplasty was adapted to all of them successfully. Post-operative echocardiography showed no tricuspid regurgitation in two patients and mild regurgitation in eight patients. The cardiothoracic ratios on their chest roentgenograms decreased from 0.59 ± 0.05 to 0.54 ± 0.05. At the latest follow-up (50.4 ± 47.2 months), echocardiography showed that mild to moderate tricuspid regurgitation in seven patients, moderate tricuspid regurgitation in three patients, and no patient with severe tricuspid regurgitation. All patients were in NYHA functional class I. CONCLUSIONS: For patients with isolated tricuspid regurgitation who were not well responsive to drug therapy, individualised tricuspid valve repair can achieve an excellent result.

Outcomes of Common Atrioventricular Valve Repair in Patients With Single-Ventricle Physiology　- Indication, Timing and Repair Techniques.

BACKGROUND: Common atrioventricular valve (CAVV) repair in patients with a single ventricle remains a great challenge and a refractory issue for pediatric cardiac surgeons. Methods and Results: From January 2007 to April 2018, 37 consecutive patients with a single ventricle who underwent CAVV repair were included in the study group. Patients were divided into 2 groups based on the repair technique: patients in Group A were treated using the bivalvation technique, and patients in Group B underwent conventional repair techniques; baseline data were similar between groups. The inhospital and follow-up mortality were 5.4% (2/37) and 11.4% (4/35), respectively. After a follow-up of 65.5±29.3 months, the estimated 1-, 5-, and 10-year overall survival rates were 94.6%, 83.4%, and 77.0%, respectively. The rates of freedom from CAVV failure were 94.3%, 72.7%, and 62.9% after 1, 5, and 10 years, respectively. In the multivariate analysis, the independent factors for CAVV repair failure were repair technique (P=0.004) and heterotaxy syndrome (P=0.003). A total of 30 patients (81.1%) completed total cavopulmonary connection (TCPC); 3 patients required re-intervention; 24 of 31 patients (77.4%) were in New York Heart Association classes II and I at the latest follow-up. CONCLUSIONS: Outcomes of CAVV repair in patients palliated by single-ventricular surgery are acceptable. The bivalvation technique is a simple and effective technique.