Pulmonary Valve Stenosis Research Articles

Accurate prediction of systolic peak-to-peak gradient in children with pulmonary valve stenosis.

Accurate prediction of systolic peak-to-peak gradient in children with pulmonary valve stenosis.

Noonan Syndrome: Relation of Genotype to Cardiovascular Phenotype-A Multi-Center Retrospective Study.

Background: Noonan syndrome (NS) is a congenital genetic disorder with a prevalence of 1 in 1000 to 2500 live births, and is characterized by distinctive facial features, short stature, chest deformities, and congenital heart disease. This study aims to evaluate the prevalence of specific genetic mutations and their impact on cardiovascular and other outcomes in NS. Methods: We conducted a retrospective clinical study of 25 pediatric patients diagnosed with NS at two institutions: The Mother and Child Health Care Institute of Serbia and the Clinic for Children Diseases, University Clinical Center of the Republic of Srpska. Patients underwent whole-exome sequencing (WES) to identify genetic mutations. Clinical data, including cardiovascular manifestations, psychomotor development, and stature, were analyzed in relation to mutation types. Results: The cohort comprised 60% male and 40% female patients, with a median age at diagnosis of 7.2 years. Cardiovascular abnormalities were present in 88% of patients. Mutations in PTPN11 were most commonly associated with pulmonary valve stenosis (PVS), while RAF1 mutations were prevalent in patients with hypertrophic cardiomyopathy (HCM). No significant association was found between cardiac disease and delayed psychomotor development (p = 0.755), even though the likelihood ratio showed significance in that regard (p = 0.018). Short stature was observed in 48% of patients but was not significantly correlated with genetic type of disease, presence of cardiac disease, or developmental delay. Conclusions: The study confirms the high prevalence of cardiovascular manifestations in NS and highlights genotype-phenotype correlations. While cardiac abnormalities are common, their impact on psychomotor development and stature is less clear. Further research is needed to explore genetic interactions influencing these outcomes and refine clinical management strategies.

Homozygous splice-site variant in ENPP1 underlies generalized arterial calcification of infancy

ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) plays a critical role by converting extracellular ATP to AMP, generating extracellular PPi, a potential inhibitor of calcification. Pathogenic variants in the ENPP1 cause generalized arterial calcification of infancy (GACI [OMIM 208000]). GACI, is an ultra-rare disease characterized by early-onset calcification of large and medium-sized arteries, leading to severe cardiovascular complications such as heart failure, pulmonary stenosis (PS), hypertension, and more. In this study, we report a novel homozygous splice-site pathogenic variant in ENPP1 (NM_006208, c.2230 + 5G > A; p.Asp701Asnfs*2) residing in C-terminal nuclease-like domain (NLD) of ENPP1 protein in a Pakistani family diagnosed with severe valvular PS and mild right ventricular hypertrophy (RVH). cDNA assays confirmed the skipping of exon 21, and the splice product underwent nonsense-mediated decay. Functional studies on fibroblasts from the patient demonstrated increased calcification and decreased enzymatic activity of ENPP1, recapitulating the hallmarks of GACI. By combining genetic analysis with the in vitro study, we substantiate that ENPP1:c.2230 + 5G > A variant is pathogenic, underscoring its role in the development of GACI.

Abstract 4120743: MEK inhibition for recurring pulmonary valve stenosis in RASopathy patients

Backgound: The RASopathies are developmental syndromes resulting from variants in the RAS/mitogen-activated protein (MAPK) cascade. The vast majority of RASopathy-causing variants lead to a gain of function in RAS-MAPK signaling. This has motivated compassionate use of MEK inhibition (MEKi) for rare, but potentially lethal complications such as hypertrophic cardiomyopathy and lymphatic disease. However, the most recurrent cardiac complication in RASopathies is pulmonary valve stenosis (PVS). PVS may require balloon valvuloplasty (BV) and can recur over time. Research question: Can MEKi be successfully used for recurrent PVS in RASopathy-patients? Aim: To report compassionate use of MEKi (trametinib) in recurring RASopathy-associated PVS. Method: Retrospective, single-center study at CHU Sainte Justine, Montreal, from 2021 to 2024. Results: After informed parental consent for off-label compassionate use of trametinib, four patients with recurrence of severe PVS after balloon valvuloplasty (>= 80 mmHg) had a total of 5 treatment episodes. Three patients were female, and one patient was male. The following genotypes were represented: Case 1, RIT1 A77V; case 2, PTPN11 N308D; case 3, RIT1 F82V, del22q11dist; case 4, PTPN11 Q110G, dup Xp22.13 (VUS), dup 16p11.2. Initial BV was carried out between three weeks and 10 months of age. Recurrence of PVS was noted between 4 days and 6 months after BV. Peak gradients at recurrence measured 72 -96 mmHg, and decreased to 40 – 64 mmHg (Dp -10 to -40 mmHg) at one to three months after treatment. Treatment had to be stopped in three cases for cutaneous side effects, with a rapid second recurrence in one case, which again responded to MEKi. PVS residual gradients at latest follow-up ranged from 30 – 69 mmHg. In all four patients, repeat catheter intervention or surgery could be avoided. In three out of four RASopathy patients with severe recurrent PVS after initial BV, we observe mild or moderate residual PVS. The patient with residual severe PS also carries a del22q11.2dist, which renders her haploinsufficient for LZTR1, a potential disease/treatment modifier within the RAS-MAPK cascade. Conclusion: Our results potentially expand the indications for MEKi in selected cases of RASopathy-associated recurrence of PVS and suggest an alternative to surgery or repeat catheterization. However, this case series is limited by the lack of an adequate contemporaneous, genotyped control cohort and its retrospective nature.

Electrical substrate of the right ventricle in valvular pulmonary stenosis: Early observations from electrophysiology studies before pulmonary valve replacement

Electrical substrate of the right ventricle in valvular pulmonary stenosis: Early observations from electrophysiology studies before pulmonary valve replacement

Surgical results of tetralogy of Fallot repair with pulmonary valve preservation techniques

The long-term complications arising from chronic pulmonary insufficiency after surgical correction of tetralogy of Fallot (TOF) are well documented. In our center, innovative techniques for pulmonary valve (PV) preservation have been adopted and developed for over 10 years. All patients with TOF and PV stenosis who underwent surgery at our center between January 2008 and December 2022 were included in this study. Patients were evaluated using echocardiography during follow-up, comparing those who underwent classic surgery with transannular patch (TAP) placement and those who underwent PV preservation techniques. Of the 134 patients, 99 (73.9%) were successfully treated using PV preservation techniques. At the time of surgery, the median age was 4.3 months (interquartile range [IQR] 3.4-5.9 months). The median preoperative PV z-score was -2.87 (IQR -3.61;-2.48). The median follow-up time from surgery was 6.6 years (IQR 3.5-8.4 years). During the median follow-up, the right ventricular area change fraction was 47% (IQR 43-50%) in patients treated with PV preservation and 43% (IQR 41-47%) in the TAP group (p=0.005). These data were associated with better PV function in patients treated with preservation. Specifically, insufficiency was mild in 12%, moderate in 35%, and severe in 53% of patients in the TAP group. Conversely, insufficiency was mild in 53%, moderate in 35%, and severe in 11% of patients treated with preservation (p<0.001). Annular integrity and PV function can be preserved during early TOF correction. PV preservation can prevent the long-term development of pulmonary insufficiency and right ventricular dysfunction.

Agreement of echocardiographic and catheterization-based methods of transpulmonary pressure gradient measurement in dogs

Introduction/ObjectivesDoppler echocardiographic estimation of transpulmonary pressure gradient (PG) is widely used to determine severity of pulmonary valve stenosis and indication for transcatheter intervention. The objective of this study was to describe agreement between Doppler echocardiographic methods of transpulmonary PG estimation and direct peak-to-peak pressure gradient at catheterization (PGcath) in dogs. We hypothesized that with reference to PGcath, mean echocardiographic PG (PGecho-mean) would have less bias than peak modal instantaneous echocardiographic PG (PGecho-peak). AnimalsClient-owned dogs with congenital pulmonary valve stenosis that underwent balloon pulmonary valvuloplasty at one of two veterinary teaching hospitals between June 2012 and May 2022 were included in this study. Materials and MethodsCases that underwent transthoracic echocardiography and subsequent balloon pulmonary valvuloplasty separated by 30 or fewer days were retrospectively identified. For each echocardiogram, average PGecho-mean (mmHg) and average PGecho-peak (mmHg) were calculated from stored spectral Doppler recordings. Peak right ventricular-to-peak pulmonary artery PG data (mmHg) were obtained from catheterization reports. Bland–Altman analysis was used to assess agreement between echocardiographic and catheterization data. ResultsData from 209 dogs (n = 215 instances) were evaluated. Proportional bias, greater at higher gradients, was observed for PGecho-mean versus PGcath (P<0.001). A constant bias of −38.12 mmHg was observed for PGecho-peak versus PGcath (P=0.62). Bias for both echocardiographic variables had wide limits of agreement that increased with PG. ConclusionsPGecho-mean and PGecho-peak underestimated and overestimated PGcath, respectively, preventing their interchangeability with PGcath.

Impact of age at intervention on three-dimensional RV functions post percutaneous pulmonary valvuloplasty

Abstract Background Pulmonary valve stenosis (PVS) is a common congenital heart disease that represents approximately 8%–10% of cardiac birth defects. Percutaneous pulmonary valvuloplasty is considered the procedure of choice whenever feasible. The impact of RV functions on outcomes in a broad range of conditions is well established, hence the importance of post-procedural long-term follow-up of RV volumes and functions. Aim and objectives To assess long-term RV functions and volumes by 3D echocardiography post-successful percutaneous pulmonary valvuloplasty and study the impact of age at intervention on 2D and 3D RV parameters. Methods We conducted a cross-sectional observational study on a cohort of 100 patients who had isolated congenital valvular pulmonary stenosis and had undergone successful balloon pulmonary valvuloplasty. The study included patients who had completed more than a year post-procedure and were present for routine follow-up echocardiography. Basic echocardiography was performed along with RV volumes and functions analysis using multi-beat full-volume 3D echocardiography. Result The study population consisted of 45 females (45.0%) and 55 males (55.0%) with ages ranging from 1.5–18 years and with a median (IQR) of [8.5 (4-10)]. 90 patients had normal RV functions by 2D RV S’, TAPSE, and FAC. By 3D analysis, RV EF was normal in 91 patients, indexed RV EDV was normal in 90 patients and high normal in 10 patients, indexed RV ESV was normal in 87 patients and high normal in 13 patients. When patients’ age at intervention was correlated to RV functions, age showed a significant negative correlation to 2D-derived as well as 3D-derived FAC and TAPSE with P values of 0.000, 0.011, 0.000, and 0.005 respectively. Moreover, age at intervention showed a positive statistically significant correlation to 3D-derived indexed RV EDV and indexed RV ESV with a P value of 0.000 and 0.000, and a significant negative correlation to 3D-derived RV EF with a P value of 0.000. Conclusion Percutaneous pulmonary valvuloplasty is an effective procedure in the long term, however, our preliminary data suggest that older age at intervention could have a negative impact on RV functions and volumes when assessed by 2D and 3D echocardiography. Further sub-analysis could be applied to confirm these findings and rule out any potential confounding factors.

Maternal prepregnancy weight as an independent risk factor for congenital heart defect: systematic review and meta-analysis stratified by subtype and severity of defect.

To assess the association between increased maternal prepregnancy body mass index (BMI) and the risk of congenital heart defect (CHD) in offspring. This systematic review and meta-analysis searched PubMed/MEDLINE, Web of Science and Scopus from inception to 20 April 2023. Risk estimates were abstracted or calculated for increased BMI categories (overweight, obesity, moderate obesity and severe obesity) compared with normal weight (reference). Fixed-effects or random-effects models were used to combine individual study risk estimates based on the degree of heterogeneity. Sensitivity analyses were conducted to weight pooled estimates for relevant moderators, particularly diabetes before and during pregnancy. Subgroup analyses for specific CHD subtypes were conducted if there were at least two studies with available data. Findings were presented for groups of defects, categorized using severity and topographic-functional criteria, and for individual defects. The certainty of the evidence for each effect estimate was evaluated according to Grading of Recommendations, Assessment, Development and Evaluation (GRADE) guidelines. Overall, 31 studies comprising 4 861 693 patients and 86 136 CHD cases were included. The risk of CHD increased progressively from moderate to severe obesity (pooled odds ratio (OR), 1.15 (95% CI, 1.11-1.20) and 1.39 (95% CI, 1.27-1.53), respectively). Sensitivity analysis indicated that this effect persisted independently of maternal diabetes status before or during pregnancy. In the subgroup analysis, obesity was associated with up to a 1.5-fold increase in the risk of severe CHD (pooled OR, 1.48 (95% CI, 1.03-2.13)). Severe obesity was associated with an even higher risk, with 1.8-times higher odds compared with the reference group for specific CHD subtypes, including tetralogy of Fallot (pooled OR, 1.72 (95% CI, 1.38-2.16)), pulmonary valve stenosis (pooled OR, 1.79 (95% CI, 1.39-2.30)) and atrial septal defect (pooled OR, 1.71 (95% CI, 1.48-1.97)). Maternal weight is a crucial modifiable risk factor for CHD, particularly for severe forms of defect. Further research is needed to investigate whether weight management before pregnancy might serve as a preventive measure against CHD. In pregnant women with obesity, fetal echocardiography should be a routine diagnostic procedure. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Carcinoid Pulmonary Valve Stenosis: Multimodality Imaging and Transcatheter Valve Implant With Prestenting Technique.

Carcinoid Pulmonary Valve Stenosis: Multimodality Imaging and Transcatheter Valve Implant With Prestenting Technique.

Balloon pulmonary valvuloplasty with percutaneous transluminal mitral commissurotomy balloon in pulmonary stenosis

Pulmonary stenosis is common and accounts for 5%–12% of all congenital heart diseases. Echocardiography is the mainstay for evaluating pulmonary stenosis due to its easy availability, reproducibility and non-invasive nature. American Heart Association/American College of Cardiology (AHA/ACC) guideline recommends balloon pulmonary valvuloplasty in patients with moderate to severe valvular pulmonary stenosis. Due to its advantages over other balloons, Inoue and Accura balloon, balloons especially designed for Percutaneous Transluminal mitral commissurotomy can be used for successful balloon pulmonary valvuloplasty.

Cardiac Phenotype and Gene Mutations in RASopathies.

Cardiac involvement is a major feature of RASopathies, a group of phenotypically overlapping syndromes caused by germline mutations in genes encoding components of the RAS/MAPK (mitogen-activated protein kinase) signaling pathway. In particular, Noonan syndrome (NS) is associated with a wide spectrum of cardiac pathologies ranging from congenital heart disease (CHD), present in approximately 80% of patients, to hypertrophic cardiomyopathy (HCM), observed in approximately 20% of patients. Genotype-cardiac phenotype correlations are frequently described, and they are useful indicators in predicting the prognosis concerning cardiac disease over the lifetime. The aim of this review is to clarify the molecular mechanisms underlying the development of cardiac diseases associated particularly with NS, and to discuss the main morphological and clinical characteristics of the two most frequent cardiac disorders, namely pulmonary valve stenosis (PVS) and HCM. We will also report the genotype-phenotype correlation and its implications for prognosis and treatment. Knowing the molecular mechanisms responsible for the genotype-phenotype correlation is key to developing possible targeted therapies. We will briefly address the first experiences of targeted HCM treatment using RAS/MAPK pathway inhibitors.

Differences in Right Heart Function After Pulmonary Valve Replacement in Patients With Pulmonary Valve Stenosis Versus Tetralogy of Fallot.

There are limited data about the impact of timing of pulmonary valve replacement (PVR) on right heart reverse remodeling in patients with pulmonary regurgitation following intervention for isolated pulmonary valve stenosis (PS). This study compared differences in postprocedural right heart reverse remodeling after early versus late PVR (defined as PVR before versus after attainment of the conservative consensus criteria proposed by Bokma etal, 2018) in patients with prior intervention for PS, using patients with tetralogy of Fallot as the reference group. Right atrial reservoir strain and right ventricular free wall strain was measured at baseline, 1 and 3 years after PVR. There were 114 patients with PS (early PVR, 87 [76%]; late PVR, 27 [24%]) and 291 patients with tetralogy of Fallot (early PVR, 197 [67%]; late PVR, 96 [33%]). The PS group had greater improvement in right atrial reservoir strain at 1 year (12%±4% versus 8%±4%; P<0.001) and 3 years (15%±6% versus 9%±6%; P<0.001), and a greater improvement in right ventricular free wall strain at 1 year (12%±4% versus 7%±3%, P=0.008) and 3-years (16%±6% versus 12%±5%; P=0.01) after PVR compared with the tetralogy of Fallot group. There was no difference in right heart reverse remodeling between patients who underwent early versus later PVR within the PS group. In contrast, late PVR was associated with less right heart reverse remodeling within the tetralogy of Fallot group. These data suggest that patients with palliated PS presenting pulmonary regurgitation have a more benign clinical course, and hence delaying PVR in this population may be appropriate.

Double outlet right ventricle accompanied by complex congenital anomalies: A rare association

Double outlet right ventricle (DORV) comprises a heterogeneous series of associated cardiac anomalies that involve the RV outflow tract in which both of the great arteries arise entirely or predominantly from the RV. The anatomic dysmorphology is variable, and there may be associated cardiac anomalies. We report here a case of a complex cyanotic heart disease in a 14 year old adolescent comprising of DORV accompanied by multiple congenital cardiac anomalies: single atrium, complete AV canal defect, severe AV valve regurgitation, D-malposition of great arteries, subaortic obstruction and pulmonary valvular stenosis.

Dysplastic Mitral Valve in Costello Syndrome

Costello syndrome is an autosomal dominant condition caused by variants in the HRAS gene. Cardiac presentation includes valvular disease (usually valvar pulmonary stenosis), arrhythmias, and hypertrophic cardiomyopathy. To our knowledge, this is the first such report of dysplastic mitral valve associated with Costello syndrome.

Cardiac screening in pediatric patients with neurofibromatosis type 1: similarities with Noonan syndrome?

Both Neurofibromatosis type 1 (NF1) and Noonan syndrome (NS) are RASopathies. Characteristic cardiac phenotypes of NS, including specific electrocardiographic changes, pulmonary valve stenosis and hypertrophic cardiomyopathy have not been completely studied in NF1. Purpose: The aims of this study were to assess: (1) similarities in the prevalence and types of ECG and conventional echocardiographic findings described in NS in asymptomatic patients with NF1, and (2) the presence of discrete myocardial dysfunction in NF1 patients using myocardial strain imaging. Methods: Fifty-eight patients with NF1 (ages 0–18 years), and thirty-one age-matched healthy controls underwent cardiac assessment including blood pressure measurements, a 12-lead ECG, and detailed echocardiography. Quantification of cardiac chamber size, mass and function were measured using conventional echocardiography. Myocardial strain parameters were assessed using 2-Dimensional (2D) Speckle tracking echocardiography. Results: Asymptomatic patients with NF1 had normal electrocardiograms, none with the typical ECG patterns described in NS. However, patients with NF1 showed significantly decreased calculated Z scores of the left ventricular internal diameter in diastole and systole, reduced left ventricular mass index and a higher incidence of cardiac abnormal findings, mainly of the mitral valve, in contrast to the frequently described types of cardiac abnormalities in NS. Peak and end systolic global circumferential strain were the only significantly reduced speckle tracking derived myocardial strain parameter. Conclusions: Children with NF1 demonstrated more dissimilarities than similarities in the prevalence and types of ECG and conventional echocardiographic findings described in NS. The role of the abnormal myocardial strain parameter needs to be explored.

Cardiac CT of Dome-shaped Pulmonary Valve Stenosis.

Cardiac CT of Dome-shaped Pulmonary Valve Stenosis.

A Novel Model for Xenograft Right Ventricle to Pulmonary Artery Conduit.

The last 40 years have shown dramatic improvement in outcomes for neonatal cardiac surgery for a spectrum of congenital heart disease diagnoses. With more patients surviving into adulthood, the long-term impact of initial management strategies of these patients has come into focus. This is particularly true for patients with pediatric heart valve disease. Many patients born with right ventricular to pulmonary artery (RVPA) discontinuity require placement of a valved conduit in the neonatal period. Valved conduit options are limited in this patient population due to patient size and inability to respond to somatic growth. Genetically engineered porcine (GEP) donors may offer a xenograft conduit alternative that can grow with the patient. We have developed a model utilizing GEP donor RVPA conduits placed in infantile nonhuman primate (NHP) recipients. Our recipient is maintained on single-drug immunosuppression and demonstrates no evidence of pulmonary valve insufficiency or stenosis during short-term follow-up. Further studies and long-term outcomes are necessary to determine the utility of this technology in human application.

Carcinoid syndrome with right-sided valve involvement - a case report and review of the literature.

The survival of patients with neuroendocrine tumors has substantially improved with modern treatment options. Although the associated carcinoid syndrome can be diagnosed early and controlled effectively, cardiologists still encounter patients with cardiac manifestations, particularly among individuals with persistently high levels of vasoactive mediators. Treatment options have been limited to surgical valve replacement in fully manifested disease. Since surgery is not always feasible, transcatheter valve implantation is becoming an interesting alternative. A case of a 50-year-old woman with carcinoid syndrome and right-sided valvular heart disease is presented. Moderate pulmonary valve stenosis and severe tricuspid valve regurgitation were diagnosed during the evaluation and treatment of neuroendocrine tumor. The possibility of rare valve involvement and the need for interdisciplinary cooperation in the diagnosis, monitoring and treatment of patients with neuroendocrine tumors producing vasoactive substances must be emphasized. The patient had a typically presenting carcinoid syndrome with a rare cardiac manifestation. Although monitoring and treatment were carried out in accordance with recommendations and appropriate to the clinical condition, rapid progression of the metastatic disease ultimately precluded invasive cardiac intervention.

Early Outcomes From a Multicenter Transcatheter Self-Expanding Pulmonary Valve Replacement Registry

BackgroundTranscatheter pulmonary valve replacement (TPVR) with the self-expanding Harmony valve (Medtronic) is an emerging treatment for patients with native or surgically repaired right ventricular outflow tract (RVOT) pulmonary regurgitation (PR). Limited data are available since U.S. Food and Drug Administration approval in 2021. ObjectivesIn this study, the authors sought to evaluate the safety and short-term effectiveness of self-expanding TPVR in a real-world experience. MethodsThis was a multicenter registry study of consecutive patients with native RVOT PR who underwent TPVR through April 30, 2022, at 11 U.S. centers. The primary outcome was a composite of hemodynamic dysfunction (PR greater than mild and RVOT mean gradient >30 mm Hg) and RVOT reintervention. ResultsA total of 243 patients underwent TPVR at a median age of 31 years (Q1-Q3: 19-45 years). Cardiac diagnoses were tetralogy of Fallot (71%), valvular pulmonary stenosis (21%), and other (8%). Acute technical success was achieved in all but 1 case. Procedural serious adverse events occurred in 4% of cases, with no device embolization or death. Hospital length of stay was 1 day in 86% of patients. Ventricular arrhythmia prompting treatment occurred in 19% of cases. At a median follow-up of 13 months (Q1-Q3: 8-19 months), 98% of patients had acceptable hemodynamic function. Estimated freedom from the composite clinical outcome was 99% at 1 year and 96% at 2 years. Freedom from TPVR-related endocarditis was 98% at 1 year. Five patients died from COVID-19 (n = 1), unknown causes (n = 2), and bloodstream infection (n = 2). ConclusionsIn this large multicenter real-world experience, short-term clinical and hemodynamic outcomes of self-expanding TPVR therapy were excellent. Ongoing follow-up of this cohort will provide important insights into long-term outcomes.