Identification of Prostaglandin I2 Synthase Rare Variants in Patients With Williams Syndrome and Severe Peripheral Pulmonary Stenosis.

BACKGROUND: Peripheral pulmonary stenosis (PPS) is a condition characterized by the narrowing of the pulmonary arteries, which impairs blood flow to the lung. The mechanisms underlying PPS pathogenesis remain unclear. Thus, the aim of this study was to investigate the genetic background of patients with severe PPS to elucidate the pathogenesis of this condition. METHODS AND RESULTS: We performed genetic testing and functional analyses on a pediatric patient with PPS and Williams syndrome (WS), followed by genetic testing on 12 patients with WS and mild-to-severe PPS, 50 patients with WS but not PPS, and 21 patients with severe PPS but not WS. Whole-exome sequencing identified a rare PTGIS nonsense variant (p.E314X) in a patient with WS and severe PPS. Prostaglandin I2 synthase (PTGIS) expression was significantly downregulated and cell proliferation and migration rates were significantly increased in cells transfected with the PTGIS p.E314X variant-encoding construct when compared with that in cells transfected with the wild-type PTGIS-encoding construct. p.E314X reduced the tube formation ability in human pulmonary artery endothelial cells and caspase 3/7 activity in both human pulmonary artery endothelial cells and human pulmonary artery smooth muscle cells. Compared with healthy controls, patients with PPS exhibited downregulated pulmonary artery endothelial prostaglandin I2 synthase levels and urinary prostaglandin I metabolite levels. We identified another PTGIS rare splice-site variant (c.1358+2T>C) in another pediatric patient with WS and severe PPS. CONCLUSIONS: In total, 2 rare nonsense/splice-site PTGIS variants were identified in 2 pediatric patients with WS and severe PPS. PTGIS variants may be involved in PPS pathogenesis, and PTGIS represents an effective therapeutic target.

Influence of right ventricular pressure and volume overload on right and left ventricular diastolic function.

BACKGROUND: Ventricular interdependence may account for altered ventricular mechanics in congenital heart disease. The present study aimed to identify differences in load-dependent right ventricular (RV)-left ventricular (LV) interactions in porcine models of pulmonary stenosis (PS) and pulmonary insufficiency (PI) by invasive admittance-derived hemodynamics in conjunction with noninvasive cardiovascular magnetic resonance (CMR). METHODS: Seventeen pigs were used in the study (7 with PS, 7 with PI, and 3 controls). Progressive PS was created by tightening a Teflon tape around the pulmonary artery, and PI was created by excising 2 leaflets of the pulmonary valve. Admittance catheterization data were obtained for the RV and LV at 10 to 12 weeks after model creation, with the animal ventilated under temporary diaphragm paralysis. CMR was performed in all animals immediately prior to pressure-volume catheterization. RESULTS: In the PS group, RV contractility was increased, manifested by increased end-systolic elastance (mean difference, 1.29 mm Hg/mL; 95% confidence interval [CI], 0.57-2.00 mm Hg/mL). However, in the PI group, no significant changes were observed in RV systolic function despite significant changes in RV diastolic function. In the PS group, LV end-systolic volume was significantly lower compared with controls (mean difference, 25.1 mL; 95% CI, -40.5 to -90.7 mL), whereas in the PI group, the LV showed diastolic dysfunction, demonstrated by an elevated isovolumic relaxation constant and ventricular stiffness (mean difference, 0.03 mL-1; 95% CI, -0.02 to 0.09 mL-1). CONCLUSIONS: The LV exhibits systolic dysfunction and noncompliance with PI. PS is associated with preserved LV systolic function and evidence of some LV diastolic dysfunction. Interventricular interactions influence LV filling and likely account for differential effects of RV pressure and volume overload on LV function.

Venous Properties in a Fontan Patient with Successful Remission of Protein-Losing Enteropathy.

We present the case of a 1-year-old boy who developed protein-losing enteropathy (PLE) within 2 months of a fenestrated Fontan procedure. His fenestration rapidly closed despite bilateral pulmonary stenosis (BPS). Subsequent to PLE onset, both fenestration and the bilateral pulmonary artery were reconstructed, and the patient's PLE had been in remission, with additive use of medications, for more than 2 years. Notably, although fenestration closed again and central venous pressure (CVP) reduction was minimal, the surrogates of venous return resistance were markedly suppressed as shown by increased blood volume, reduced estimated mean circulatory filling pressure, and suppressed CVP augmentation against a contrast agent. Taken together, dynamic characteristics of venous stagnation, rather than the absolute value of CVP, were ameliorated by the pulmonary reconstruction and use of medications, suggesting a significant role of venous property in the physiology of PLE. In addition, simultaneous measures of CVP and ventricular end-diastolic pressure during the abdominal compression procedure suggested a limited therapeutic role of fenestration against PLE in this patient.

The behavior of residual pulmonary artery gradient after arterial switch operation: A longitudinal data analysis.

OBJECTIVE: The arterial switch operation (ASO) is the standard treatment for the transposition of the great arteries. The timely variation in the residual pressure gradient across the pulmonary arteries is ill-defined. This study is aimed to study the progressive changes in the pressure gradient across the pulmonary valve and pulmonary arteries after ASO. METHODS: All eligible patients for this study who underwent ASO between 2000 and 2019 were reviewed. Transthoracic echocardiography was used to estimate the peak pressure gradient across the pulmonary artery and its branches. The primary outcome was the total peak pressure gradient (TPG) which is the sum of peak pressure gradients across the main pulmonary artery and pulmonary artery branches. Furthermore, longitudinal data analyses with mixed-effect modeling were used to determine the independent predictors for the changes in the pressure gradient. RESULTS: Three hundred and nine patients were included in the study. Over a 17-year follow-up, the freedom from pulmonary stenosis reintervention was 95% (16 out of the 309 patients underwent reintervention = 5%). The longitudinal data analyses of serial 1844 echocardiographic studies for the included patients revealed that the TPG recorded in the first postoperative echocardiogram across pulmonary valve, right and left pulmonary artery branches was the most significant predictor for reintervention. CONCLUSION: The total peak gradient measured in the first postoperative echocardiogram is the most important predictor for reintervention. We propose that a total peak gradient in the first postoperative echocardiography of 55 mm Hg or more is a predictor for reintervention.

Balloon Valvuloplasty to Treat Adult Symptomatic Pulmonary Valve Stenosis with Sequential Follow-Up Using Cardiac Magnetic Resonance Imaging in Combination with Echocardiography.

Pulmonary valve stenosis (PVS) accounts for approximately 10% of all congenital heart defects. Echocardiography and right heart catheterization are the gold standards for diagnosis of PVS and for assessing disease severity and responsiveness to treatment.Recently, cardiac magnetic resonance imaging (cMRI) has been established as an important tool to comprehensively evaluate cardiac structure and function; however, research into the usefulness of cMRI for PVS management is limited. Here, we describe a case of a 59-year-old female with isolated, severe PVS who was successfully treated with balloon pulmonary valvuloplasty (BPV) followed by sequential cMRI at 1 and 12 months. Exertional dyspnea and elevated plasma BNP concentration were observed 1 month after BPV; however, echocardiographic findings did not indicate recurrent stenosis or increased pulmonary valve regurgitation but an increase in mitral E/e'. cMRI demonstrated improved systolic forward flow and RV function with enlargement of LV volume, and the rapid increase in LV preload might be associated with the transient deterioration in symptoms and BNP level, which both gradually improved within 3 months after BPV. cMRI further depicted that a reduced RV mass index and increased RV cardiac output were achieved gradually during the follow-up period.In conclusion, cMRI in combination with echocardiography was sufficiently informative to follow-up this PVS patient both before and after BPV. cMRI is easily reproducible in adult patients; therefore, cMRI should be recommended for long-term follow-up in adult PVS patients.

Biventricular myocardial adaptation in patients with repaired tetralogy of Fallot: Mechanistic insights from magnetic resonance imaging tissue phase mapping.

BACKGROUND: The myocardial adaptive mechanism in patients with repaired tetralogy of Fallot (rTOF) is less understood. We aimed to investigate biventricular myocardial adaptive remodeling in rTOF patients. METHODS: We recruited 32 rTOF patients and 38 age- and sex-matched normal controls. The pulmonary stenosis of rTOF patients was measured using catheterized pressure gradient between right ventricle (RV) and pulmonary artery (PGRVPA). rTOF patients with PGRVPA < 15 mmHg and ≥15 mmHg were classified as low pulmonary stenosis (rTOFlow, n = 19) and high pulmonary stenosis (rTOFhigh, n = 13) subgroups, respectively. Magnetic resonance imaging tissue phase mapping was employed to evaluate the voxelwise biventricular myocardial motion in longitudinal (Vz), radial (Vr), and circumferential (Vφ) directions. RESULTS: The rTOFlow subgroup presented higher pulmonary regurgitation fraction than rTOFhigh subgroup (p < 0.001). Compared with the normal group, only rTOFlow subgroup presented a decreased RV ejection fraction (RVEF) (p < 0.05). The rTOFlow subgroup showed decreased systolic and diastolic Vz in RV and LV, whereas rTOFhigh subgroup showed such change only in RV. In rTOFlow subgroup, RVEF significantly correlated with RV systolic Vr (r = 0.56, p < 0.05), whereas LVEF correlated with LV systolic Vz (r = 0.51, p = 0.02). Prolonged QRS correlated with RV systolic Vr (r = -0.58, p < 0.01) and LV diastolic Vr (r = 0.81, p < 0.001). No such correlations occurred in rTOFhigh subgroup. CONCLUSIONS: The avoidance of unfavorable functional interaction in RV and LV in rTOFhigh subgroup suggested that adequate pulmonary stenosis (PGRVPA ≥ 15 mmHg in this sereis) has a protective effect against pulmonary regurgitation.

The progression of an acceptable pulmonary stenosis immediately after total correction of tetralogy of Fallot.

BACKGROUND: A certain degree of pulmonary stenosis after total correction of tetralogy of Fallot has been considered acceptable. But the long-term outcomes are not well understood. We observed the natural course of immediate pulmonary stenosis and investigated related factors for progression. METHODS: Fifty-two patients with acceptable pulmonary stenosis immediately after operation were enrolled. Acceptable pulmonary stenosis was defined as peak pressure gradient between 15 and 45 mmHg by Doppler echocardiography. Latent class linear mixed model was used to differentiate patients with progressed pulmonary stenosis, and the factors related to progression were analysed. RESULTS: Pulmonary stenosis progressed in 14 patients (27%). Between the progression group and no progression group, there were no significant differences in operative age, sex, and the use of the transannular patch technique. However, immediate gradient was higher in the progression group (32.1 mmHg versus 25.7 mmHg, p = 0.009), and the cut-off value was 26.8 mmHg (sensitivity = 65.3%, specificity = 65.8%). Main stenosis at the sub-valve was observed more frequently in the progression group (85.7% versus 52.6%, p = 0.027). Despite no difference in the preoperative pulmonary valve z value, the last follow-up pulmonary valve z value was significantly lower in the progression group (-1.15 versus 0.35, p = 0.002). CONCLUSIONS: Pulmonary stenosis immediately after tetralogy of Fallot total correction might progress in patients with immediate pulmonary stenosis higher than ≥26.8 mmHg and the main site was sub-valve area.

Haploinsufficiency of the basic helix-loop-helix transcription factor HAND2 causes congenital heart defects.

Congenital heart defects (CHDs) are caused by a disruption in heart morphogenesis, which is dependent, in part, on a network of transcription factors (TFs) that regulate myocardial development. Heterozygous sequence variants in the basic helix-loop-helix TF gene heart and neural crest derivatives expressed 2 (HAND2) have been reported among some patients with CHDs; however, HAND2 has not yet been established as a Mendelian disease gene. We report a 31-month-old male with unicommissural unicuspid aortic valve, moderate aortic stenosis, and mild pulmonic stenosis. Chromosome analysis revealed a normal 46,XY karyotype, and a CHD sequencing panel was negative for pathogenic variants in NKX2.5, GATA4, TBX5, and CHD7. However, chromosomal microarray (CMA) testing identified a heterozygous 546.0-kb deletion on chromosome 4q34.1 (174364195_174910239[GRCh37/hg19]) that included exons 1 and 2 of SCRG1, HAND2, and HAND2-AS1. Familial CMA testing determined that the deletion was paternally inherited, which supported a likely pathogenic classification as the proband's father had previously undergone surgery for Tetralogy of Fallot. The family history was also notable for a paternal uncle who had previously died from complications related to an unknown heart defect. Taken together, this first report of a HAND2 and HAND2-AS1 deletion in a family with CHDs strongly supports haploinsufficiency of HAND2 as an autosomal dominant cause of CHD.

Early clinical experience with the straight design of Venus P-valve™ in dysfunctional right ventricular outflow tracts.

OBJECTIVES: To assess the initial procedural and short to medium-term experience with the straight design of the Venus P-valve™ (Venus MedTech, Hangzhou, China) in dysfunctional right ventricular outflow tracts (RVOT). BACKGROUND: The Melody™ valve (Medtronic, Minneapolis, Minnesota) has been the only percutaneous valve option for smaller RVOT conduits. The straight Venus P-valve™ may provide an alternative to the Melody™ valve. METHODS: Retrospective data collection of patient characteristics, procedural data, clinical and imaging follow-up of the straight Venus P-valve™. RESULTS: Nine patients (four female) with a mean age of 23.1 ± 7.5 years and a mean weight of 72.7 ± 29.4 kg underwent straight Venus P-valve™ implantation between 03/2014 and 06/2016. All patients had right ventricle-to-pulmonary artery conduits which were pre-stented before the valve implantation. All valves were deployed successfully without any significant procedural complications. During the mean follow-up of 24 ± 9.1 months, there were no valve related re-interventions or deterioration in valve performance. There was one case of insignificant, single wire frame fracture and no cases of endocarditis. The cohort demonstrated a reduction in pulmonary regurgitation and tricuspid regurgitation, which was sustained throughout the follow-up. Similarly the gradient across the RVOT tract did not significantly increase. CONCLUSIONS: Implantation of the straight Venus P-valve™ has provided satisfactory short to mid-term results with high success rates and no complications and may be considered as an alternative option in patients with RVOT dysfunction.

Utility of the long DrySeal sheath in facilitating transcatheter pulmonary valve implantation with the Edwards Sapien 3 valve.

OBJECTIVE: To assess the utility of the 65-cm-long Gore DrySeal sheath when compared to the standard 36-cm-long Edwards expandable sheath (e-sheath) for transcatheter pulmonary valve implantation (TPVI) with the Edwards Sapien 3 valve. METHODS: All patients who underwent TPVI with the Sapien 3 valve, excluding those performed via hybrid approach, at our center between September 2015 and November 2019 were retrospectively reviewed and compared between two groups. RESULTS: A total of 94 patients were enrolled; 29 patients underwent TPVI with the Sapien valve using the DrySeal sheath and 65 underwent TPVI using the e-sheath. The height and body weight of patients implanted using the DrySeal sheath ranged from 137 to 193 cm and from 33 to 129 kg, respectively. Valve delivery time was significantly shorter in the DrySeal group (median time 4 min 33 s vs. 9 min 6 s, p = .002). There were no complications in the DrySeal group (0/27). Nine procedural complications occurred in the e-sheath group (9/65), five of which were potentially directly related to sheath choice, including tricuspid valve injury in four and embolization of the tip of the e-sheath during retrieval of a ruptured balloon in one patient. CONCLUSIONS: TPVI with the Sapien 3 valve using the 65-cm-long DrySeal sheath facilitates faster and safer valve implantation when compared to the e-sheath.

Long-term durability of bioprosthetic valves in pulmonary position: Pericardial versus porcine valves.

OBJECTIVES: The long-term durability of the 2 most commonly used types of bioprosthetic valves in the pulmonic position, the porcine and pericardial valves, is unclear. We compared the long-term durability of the pericardial (Carpentier-Edwards PERIMOUNT [CE]) and porcine (Hancock II) valves in the pulmonic position in patients with congenital cardiac anomalies. METHODS: We retrospectively reviewed the medical records of 258 cases (248 patients) of pulmonary valve implantation or replacement using CE (129 cases, group CE) or porcine (129 cases, group H) valves from 2 institutions between 2001 and 2009. RESULTS: The patients' age at pulmonary valve implantation was 14.9 ± 8.7 years. No significant differences in perioperative characteristics were observed between groups CE and H. Follow-up data were complete in 219 cases (84.9%) and the median follow-up duration was 10.5 (interquartile range, 8.4∼13.0) years. Ten mortalities (3.9%) occurred. Sixty-four patients underwent reoperation for pulmonary valve replacement due to prosthetic valve failure; 10 of these 64 patients underwent reoperation during the study period. Patients in group CE were significantly more likely to undergo reoperation (hazard ratio, 2.17; confidence interval, 1.26-3.72; P = .005) than patients in group H. Patients in group CE showed had a greater prosthetic valve dysfunction (moderate-to-severe pulmonary regurgitation or pulmonary stenosis with ≥3.5 m/s peak velocity through the prosthetic pulmonary valve) rate (hazard ratio, 1.83; confidence interval, 1.07-3.14; P = .027) than patients in group H. CONCLUSIONS: Compared with the pericardial valve, the porcine valve had long-term advantages in terms of reduced reoperation rate and prosthetic valve dysfunction in the pulmonic position in patients with congenital cardiac anomalies.

A stented bovine pericardial prosthesis in the pulmonary position.

BACKGROUND: Pulmonary valve replacement is very common among patients with congenital heart disease. The Carpentier Edwards Perimount valve (Edwards Lifesciences, Irvine, Calif), which was originally designed for the aortic position is among the most implanted valves. We aim to describe the follow-up of this valve in the pulmonary position. METHODS: Patients with a Perimount valve implanted between 2003 and 2013 in the University Medical Center Groningen were followed for the primary end point reintervention, defined as surgical or transcatheter valve replacement. Secondary end point was the occurrence of valve failure, defined as significant valvular regurgitation or stenosis. Explanted valves were histologically examined. RESULTS: Forty-five patients (median age at operation 27.8 years, 55.6% women) had a mean follow-up duration of 5.8 ± 3.3 years. There were 7 reinterventions (5 surgical and 2 transcatheter). Freedom from reintervention was respectively 95% ± 4% and 83% ± 8% at 5- and 10- years of follow-up. Freedom from valve failure was 75% ± 4% at 2 years, 65% ± 8% at 5 years of follow-up and 57% ± 10% at 10 years of follow-up. Morphology evaluation (n = 4) showed stiffened valves in the open position, with extensive fibrous tissue overgrowth on the leaflets and a variable proliferation of myofibroblasts. CONCLUSIONS: The Perimount valve has adequate function in the pulmonary valve position at 5 years of follow-up, although after 10 years of follow-up valve failure and reinterventions are common. Explanted valves show retraction and stiffening of the leaflets due to a fibrotic layer on both sides of the leaflet.

Pulmonary Valve Function Late After Ross Procedure in 443 Adult Patients.

BACKGROUND: Limited data exist on long-term pulmonary valve function after the Ross procedure. This study sought to determine the long-term function of the pulmonary valve in 443 consecutive adult patients who underwent a Ross procedure. METHODS: All 443 patients who underwent a Ross procedure between November 1992 and March 2018 were reviewed retrospectively. All underwent pulmonary valve replacement using a cryopreserved pulmonary allograft. Freedom from the study's outcomes were calculated using Kaplan Meier survival. Risk factors for valve failure were analyzed using Cox regression. RESULTS: Mean age at time of operation was 39 years (range: 15-66 years). There was 1 (0.2%, 1 of 443) operative mortality. Nine patients required reintervention on the pulmonary allograft at a mean 6.1 years (range: 1-12 years) after Ross procedure. Patients required pulmonary allograft reintervention for infective endocarditis (n = 4), severe pulmonary stenosis (n = 4), or severe pulmonary regurgitation (n = 1). Freedom from pulmonary allograft reintervention was 98.9% (95% confidence interval [CI] 97.1%-99.6%), 97.7% (95% CI 95.1%-98.9%), 96.6% (95% CI 93.3%-98.3%), and 96.6% (95% CI 93.3%-98.3%) at 5, 10, 15, and 20 years, respectively. Freedom from pulmonary allograft dysfunction (at least moderate pulmonary regurgitation and/or mean systolic gradient ≥ 25 mm Hg and/or reintervention) was 94.5% (95% CI 91.6%-96.4%), 88.1% (95% CI 83.6%-91.4%), 84.9% (95% CI 79.6%-88.9%), and 78.3% (95% CI 69.5%-84.9%) at 5, 10, 15, and 20 years, respectively. No risk factors were identified to influence pulmonary valve durability. CONCLUSIONS: The pulmonary valve allograft gives excellent long-term function when used in adults undergoing the Ross procedure. Reintervention on the pulmonary valve is rare and significant pulmonary allograft dysfunction is uncommon.

Pulmonary balloon valvuloplasty in a pregnant woman with severe pulmonary stenosis.

Pulmonary valvular stenosis is a rare valvular disease; it accounts for 7% to 12% of all patients with congenital heart disease. Patients with mild or moderate pulmonary stenosis (PS) are usually asymptomatic and the stenosis is often detected incidentally with echocardiography performed for another reason. Severe PS typically presents with symptoms related to increased right ventricular pressure and right heart failure. Valvular heart diseases are associated with increased morbidity and mortality in pregnancy due to cardiovascular alterations that occur during the gestational period, such as increased extracellular volume, a faster heart rate, and decreased venous return due to compression of the vena cava inferior by the enlarged uterus. While mild or moderate PS can be well tolerated in pregnancy, severe PS can lead to maternal and fetal perinatal complications. Presently described is the case of a pregnant patient with severe PS who successfully underwent balloon valvuloplasty in the third trimester.

Risk factors for infective endocarditis following transcatheter pulmonary valve replacement in patients with congenital heart disease.

OBJECTIVES: We sought to delineate the risk factors for infective endocarditis (IE) in patients undergoing transcatheter pulmonary valve replacement (TCPVR). BACKGROUND: Despite the therapeutic benefits of TCPVR for treatment of dysfunctional right ventricular outflow tracts, IE is a major complication of the approach. Specific hemodynamic gradients and patient immune status as predisposing factors for IE are largely unexplored. METHODS: We performed a retrospective review of patients who had undergone TCPVR at UCLA between October 2010 and October 2017. Cases of IE were diagnosed based on the modified Duke criteria. RESULTS: Two hundred and thirty-five cases of TCPVR were performed with a mean follow-up of 2.6 years (range 0.0-8.0 years). Sixteen distinct IE events developed in 13 patients (Melody™ n = 12, SAPIEN n = 1), with a median time from implant to IE of 3.3 years (range 2.0-7.2 years). Univariate Cox regression showed that immunocompromised status was significantly associated with the development of IE hazard ratios (HR 5.43 [1.80-16.4], p = .003). Kaplan-Meier curves show that the 5-year freedom from IE among immunocompetent patients was 87% (95% CI 78-96%) versus 64% (95% CI 39-89%) among immunocompromised patients (log-rank p = .02). Postimplant right ventricular systolic pressure was higher among immunocompromised patients (p = .03). The risk of IE post-TCPVR in immunocompromised patients with residual pulmonary stenosis was 43%. CONCLUSIONS: Among the risk factors examined in this study, immunocompromised status was the most significant predictor of IE development post-TCPVR. Patients with the lowest risk of IE are those with competent immune systems, without a history of IE, and with minimal residual pulmonary valve gradients post-TCPVR.