Pulmonary Artery Banding Research Articles

Abstract 4144530: IL-37 promotes resolution of Right Heart Disease-induced inflammation and atrial fibrillation.

INTRODUCTION: Atrial Fibrillation (AF) is the most common cardiac arrhythmia. Hypertension, obesity, diabetes or right heart disease (RHD) are important risk factors for AF. Inflammation stands as a common denominator among most AF risk factors. Studies have shown that patients with AF present high levels of circulating IL-18. Our group recently described that inflammation-resolution may prevent AF in RHD, however, the mechanism remains unclear. To inhibit IL-18-induced inflammation, IL37, a specific antagonist of IL-18-receptor was shown to attenuate cardiac fibrosis in a mice model of myocardial infarction, but little is known about its efficacy to prevent AF. HYPOTHESIS: IL-37 curbs RHD-induced atrial inflammation and AF vulnerability. METHODS: To induce right-sided cardiac hypertrophy and dilation, pulmonary artery banding (PAB) was performed in male and female Wistar rats (250-300g). Sham animals did not receive the ligation. Animals were randomized into four groups: Sham and PAB treated or not with IL37 (100 ng/ml/kg). Electrophysiological studies and echocardiography were performed in vivo before sacrifices at day (D)0, D7, D14 and D21. To analyze the atrial conduction, right atrial (RA) optical mapping was performed on Langendorff-perfused hearts. Histology, western blot, and qPCR were performed to study the expression of proteins and genes involved in atrial inflammation, fibrosis, and electrical remodeling. RESULTS: Twenty-one days after surgery, PAB rats were more vulnerable to AF and developed severe right-sided hypertrophy and dilation compared to Sham. Reliable to clinical evidence, female rats might be more resistant to AF than males. AF was associated with increased RA levels of inflammatory biomarkers including IL18, IL1β, and IL6. IL37 treatment was associated with decreased atrial expression of inflammatory markers. CONCLUSION: IL37 is a potential new therapeutic strategy to reduce atrial inflammation and prevent AF vulnerability in RHD.

Interleukin-22 inhibits right ventricular remodelling by a unique mechanism in a pulmonary artery constriction model

Abstract Background Fibrosis and remodeling of right ventricle (RV) are associated with prognosis in patients with RV failure. Interleukin-22 (IL-22) is a member of the IL-10 cytokine family, play roles in tissue protection and wound repair. We have previously shown that IL-22 plays an important role in cardiac remodeling after acute myocardial infarction; however, the role of IL-22 in RV fibrosis and remodeling remains elusive. Purpose We investigated the role of IL-22 in the pathogenesis of RV remodeling during pressure overload. Methods Pulmonary artery banding (PAB) is performed by placing a 6-0 suture around the pulmonary artery over a 24 G needle in wild type mice (C57BL/6J) and IL-22 knockout mice (IL-22 KO). Only mice with moderate pulmonary artery stenosis (peak pressure gradient across the pulmonary band: 25–40 mmHg at 1 week after surgery by echo Doppler) were included in the study protocol. Four weeks after PAB, RV function was measured by echocardiography and real-time PCR analysis was performed to measure Col1a1, Col3a1, BNP, and transcriptome analysis was performed. Survival confirmation of mice with moderate pulmonary artery stenosis was also performed up to 56 days. Results IL-22 KO mice had significantly higher 56-day mortality rate compared with WT mice after PAC (p<0.01). Four weeks after PAB, IL-22 KO mice showed markedly increased RV weight (IL-22 KO mice vs. wild-type mice; RV/LV+IVS: 0.48±0.05 vs 0.40±0.02, P=0.002). IL-22 KO mice exhibited significant RV enlargement and RV dysfunction 4 weeks after PAB. (IL-22 KO mice vs wild type mice; RVEDV: 10±2.3mm2 vs 12.9±3.1mm2, P=0.005, TAPSE: 10.8±1.8mm vs 9.5±1.7mm, P=0.04, FAC: 35.2±7.8% vs 23±6.0%, P<0.001). The expressions of Col1a1 and Col3a1 were no difference between in IL22-KO mice and Wild mice. However, BNP, a cardioprotective marker, tended to be lower in IL-22KO mice. The transcriptome analysis also showed that the group of fibrosis-related genes that are elevated in PAC in WT mice were less elevated in IL-22 KO mice. Conclusion These results suggest that IL-22 is involved in RV remodelling during RV pressure loading without a general mechanism.

RKER-012, a novel modified ActRIIB ligand trap, attenuated right ventricular cardiomyopathy in a preclinical model of pulmonary arterial hypertension

Abstract Background The primary cause of death in pulmonary arterial hypertension (PAH) is right ventricular (RV) failure. Initially, the RV adapts to heightened pressure through adaptive remodeling, but prolonged pressure overload triggers maladaptive remodeling, culminating in failure. Overactive activin/growth differentiation factor (GDF) signaling has been implicated in cardiomyopathy and heart failure. RKER-012, a research version of KER-012, is an investigational modified activin receptor type IIB (ActRIIB) ligand trap designed to specifically bind and inhibit select TGF-β ligands, including activins A and B and GDFs 8 and 11. RKER-012 previously exhibited a cardioprotective effect in a pulmonary arterial banding (PAB) model of RV dysfunction. To determine the effect of RKER-012 on afterload-induced RV cardiomyopathy caused by increased pulmonary artery pressure, we utilized an angio-obliterative Sugen/hypoxia (SH) rat model of PAH that closely mimics human PAH pathology. Methods Male Sprague Dawley rats were subcutaneously (s.c.) injected with one dose of Sugen 5416 and exposed to 10% hypoxia for 3 weeks during which they received either vehicle (SH-Veh; s.c; BIW) or RKER-012 (10 mg/kg; s.c; BIW). Normoxic (Nx) control rats were maintained in room air for 3 weeks with BIW s.c. vehicle treatment. After 3 weeks of treatment, systolic pulmonary arterial pressure (sPAP) and Fulton index (FI) were assessed. Hallmark genes of inflammatory process, endothelial/platelet activation, and fibrosis were evaluated in the RV by qPCR. Results Increases in FI (+99.4%;p<0.0001) and sPAP (+250.9%;p<0.0001) were observed in SH-Veh rats vs. Nx rats, consistent with the development of pulmonary and cardiac impairment. In contrast, treatment with RKER-012 reduced FI (-28.0%;p<0.001) and sPAP (-44.5%;p<0.001). In the RV, SH-Veh rats had increased expression of TGF-ß pathway genes involved in inflammation, endothelial/platelet activation, and fibrosis. RKER-012 treatment reduced expression of these genes (Tgf-β1, -44.7%;p=0.003; Fstl3, -43.5%;p=0.0162; Mcp1, -22.5%;p=0.535; Cd68, -60.3%;p=0.0048; Ctgf, -57.1%;p=0.0139; Col1a1, -47.2%, p=0.0255 ;Col3a1, -69.5%;p<0.0001; Lox, -61.4%;p=0.0054; P-selectin, -63.9%;p=0.018) in comparison to SH-Veh treatment. Conclusion Consistent with previous findings in a PAB mouse model, RKER-012 treatment protected against increased sPAP and maladaptive cardiac remodeling in a SH rat model of PAH. Additionally, RKER-012 attenuated RV cardiomyopathy by reducing the expression of genes involved in inflammatory and fibrotic processes. These preclinical findings in the RV paralleled the changes in circulating cardiovascular health biomarkers, including reduced NT-proBNP, observed in a Phase 1 trial of KER-012 in healthy volunteers. These findings, along with the safety and tolerability observed in the Phase 1 trial, provided rationale for the ongoing Phase 2 TROPOS trial of KER-012 in patients with PAH (NCT05975905).

CILP1 and NTproBNP in pulmonary hypertension and right ventricular pressure overload: a translational experimental study

Abstract Introduction Cartilage intermediate layer protein 1 (CILP1) has emerged as a novel marker of right ventricular (RV) dysfunction in pulmonary hypertension (PH), although there is still little evidence on its role in different scenarios of RV pressure overload. The aim of our study was to analyze CILP1 as a biomarker of RV remodeling and PH severity, and compare it with N-terminal pro-brain natriuretic peptide (NTproBNP), in different experimental models of RV pressure overload. Methods Three different experimental models of RV pressure overload compared to a sham procedure were evaluated in 24 Yucatan pigs: chronic postcapillary PH by pulmonary vein banding (M1, n=6); chronic PH by aorto-pulmonary shunting (M2, n=6); RV pressure overload by PA banding (thus without PH) (M3, n=6); and sham procedure (M0, n=6). Animals were evaluated at 8 months after surgery by right heart catheterization, cardiac magnetic resonance (CMR), and blood/histological sampling. Levels of CILP1 and NTproBNP at the RV myocardium and blood were determined with dedicated ELISA and compared among groups by Wilcoxon test with Bonferroni correction. Associations between biomarkers and RV performance indices and pulmonary arterial pressure (PAP) were assessed with Spearman correlation test. Results M1 animals developed chronic postcapillary PH with normal left ventricular (LV) performance and RV maladaptive hypertrophy (RV fibrosis and systolic dysfunction). M2 animals developed chronic precapillary PH associated with LV dilatation and RV maladaptive hypertrophy. On contrast, M3-animals developed severe RV pressure overload (without PH) and hypertrophy but maintained normal RV systolic function. CILP1 and NTproBNP levels were moderately correlated (R=0.56, p=0.002). CILP1 levels in RV myocardium and plasma were significantly higher in M1, whereas NTproBNP plasma levels were significantly higher in M2 (Figure 1). CILP1 in plasma and RV myocardium significantly correlated with PAP, while myocardial CILP1 levels also correlated with RV extracellular volume (RV-ECV) by CMR (Figure 2). NTproBNP myocardial levels correlated with RV ejection fraction and RV-ECV and plasmatic levels correlated with PAP (Figure 2). Conclusions CILP1 levels were increased in the presence of PH and isolated RV dysfunction, whereas NTproBNP levels were increased in the model of PH, RV dysfunction and LV remodeling. Myocardial levels of both peptides correlated with diffuse fibrosis, estimated by CMR, whereas plasmatic levels of both biomarkers correlated with PAP. This suggests that CILP1 may be a more specific marker of RV dysfunction in PH, being less dependent of LV parameters.CILP1 and NTproBNP levels among modelsCorrelation with PAP & RV remodeling

Revived Role of Pulmonary Artery Band in Management of Heart Failure in Pediatric Dilated Cardiomyopathy.

Lack of appropriate durable Ventricular Assist Devices (VADs) that can be managed at home for very young children, and long wait times for transplant have led to search for alternate easily reproducible therapies. In the past decade or more, pulmonary artery banding (PAB), as a new indication of an old technology, has been gradually carried out worldwide as an alternative to mechanical circulatory support in children with end-stage left ventricular dilated cardiomyopathy (DCM) complicated with heart failure(HF), and has achieved encouraging early and mid-term outcomes. Technically, PAB is simple, safe, and effective. This is a promising therapeutic strategy, especially in developing countries where heart transplantation is difficult to implement. As a transition before transplantation, and even a potential treatment, PAB brings more options and hope for children with heart failure who are waiting for transplantation and are refractory to drug therapy. This article reviews the past and current situation, the mechanism, the surgical timing, and application prospect of PAB in the treatment of DCM complicated with heart failure.

Serial and regional assessment of the right ventricular molecular and functional response to pressure-loading.

Right ventricular(RV) function determines outcomes in RV pressure-loading. A better understanding of the time-course and regional distribution of RV remodeling may help optimize targets and timing for therapeutic intervention. We sought to characterize RV remodeling between zero and 6-weeks after initiation of RV pressure-loading. Thirty-six rats were randomized to either sham surgery or to pulmonary artery banding(PAB). After echocardiography and conductance catheter studies, groups of rats were euthanized at 1-week, 3-weeks and 6-weeks after sham surgery, or induction of RV pressure-loading, for RV histological, RNA and molecular analysis. A vigorous inflammatory response characterized by increased RV inflammatory cytokines, chemokines and macrophage markers was observed at 1-week following PAB. Metabolic changes, TGF-β1 canonical signaling, collagenous fibrosis deposition and apoptosis were already significantly increased by 1-week after PAB. Genes marking fibroblast activation were upregulated at 1-week but not 6-week post-PAB surgery. Mitochondrial dysfunction as evidenced by increased PDK activity and decreased PDH phosphorylation significantly at 6-week post PAB. These processes preceded the development of overt myocardial hypertrophy and impaired echo parameters of systolic and diastolic function which occurred significantly from 3-weeks after PAB. RV myocardial inflammation, metabolic shift, metabolic gene transcription and pro-fibrotic signaling occur early after initiation of pressure-loading when RV pressures are only moderately elevated, before the development of overt myocardial hypertrophy and dysfunction, suggesting that adaptive hypertrophy and maladaptive remodeling occur simultaneously. These results suggest that therapeutic intervention to reduce adverse RV remodeling may be needed earlier and at lower thresholds than currently employed.

Surgical Closure of Multiple Muscular Ventricular Septal Defects in Children Using 3D-Printed Models.

Multiple muscular ventricular septal defects (VSDs) are often difficult to visualize and access surgically. The main challenge is identifying all defects intraoperatively, without which residual defects are inevitable. Patient-specific three-dimensional (3D) printed models can help accurately demonstrate intracardiac anatomy. We present our experience using this technology to surgically close multiple muscular VSDs . Data of all patients with multiple VSDs in whom a 3D-printed model was used to aid surgical planning between September 2021 and July 2023 was collected retrospectively. Our approach involved generating a 3D model from a preoperative computerized tomography scan for each patient, which was then used to precisely identify the location of the multiple VSDs and plan surgical intervention. Six patients underwent closure of multiple VSDs using a 3D model. The mean age at surgery was 3.5 years (SD ± 2.8 years). Five (83.3%) patients had previously undergone pulmonary artery banding. The VSDs were approached through the right atrium in three (50%) and the right ventricle in three (50%) patients. Mean cardiopulmonary bypass and myocardial ischemia times were 185.2 min (SD ± 94.8 min) and 147.5 min (SD ± 86 min), respectively. There was no postoperative heart block or a hemodynamically significant residual VSD. All six patients had normal biventricular function at a median follow-up duration of 1.7 months (interquartile range: 1.2-7.4 months). 3D printing to aid closure of multiple VSDs is safe, reliable, and reproducible. We recommend adding 3D printing to surgeons' armamentarium when faced with the challenge of closing multiple muscular VSDs in children.

Mobile health monitoring of children with CHDs.

Mobile health has been shown to improve quality, access, and efficiency of health care in select populations. We sought to evaluate the benefits of mobile health monitoring using the KidsHeart app in an infant CHD population. We reviewed data submitted to KidsHeart from parents of infants discharged following intervention for high-risk CHD lesions including subjects status post stage 1 single ventricle palliation, ductal stent or surgical shunt, pulmonary artery band, or right ventricular outflow tract stent. We report on the benefits of a novel mobile health red flag scoring system, mobile health growth/feed tracking, and longitudinal neurodevelopmental outcomes tracking. A total of 69 CHD subjects (63% male, 41% non-white, median age 28 days [interquartile range 20, 75 days]) were included with median mobile health follow-up of 137 days (56, 190). During the analytic window, subjects submitted 5700 mobile health red flag notifications including 245 violations (mean [standard deviation] 3 ± 3.96 per participant) with 80% (55/69) of subjects submitting at least one violation. Violations precipitated 116 interventions including hospital admission in 34 (29%) with trans-catheter evaluation in 15 (13%) of those. Growth data (n = 2543 daily weights) were submitted by 63/69 (91%) subjects and precipitated 31 feed changes in 23 participants. Sixty-eight percent of subjects with age >2 months submitted at least one complete neurodevelopment questionnaire. In our initial experience, mobile health monitoring using the KidsHeart app enhanced interstage monitoring permitting earlier intervention, allowed for remote tracking of growth feeding, and provided a means for tracking longitudinal neurodevelopmental outcomes.

Impact of left ventricular rehabilitation on surgical outcomes in patients with borderline left heart hypoplasia

ObjectiveClinical significance of left ventricular (LV) rehabilitation for borderline left ventricular (LV) hypoplasia is controversial. This study aimed to review the surgical results of patients with borderline LV hypoplasia, and to evaluate the impact of the LV rehabilitation on outcomes. MethodsPatients diagnosed with borderline LV hypoplasia and surgically treated from 2018 to 2022 were included. Overall surgical outcomes were evaluated and the changes in LV volumes calculated using angiography and zlog-NT-proBNP levels were analyzed in patients who underwent LV rehabilitation. ResultsThirty-three patients were included. Sixteen patients underwent primary biventricular repair, three patients underwent primary single ventricle palliation, and the remaining 14 patients underwent LV rehabilitation, including nine bilateral pulmonary artery banding (PAB) and ductal stenting, four central PAB, and one ductal stenting. Among fourteen patients who received LV rehabilitation, one died, one underwent single ventricle palliation, one was waiting for further procedure, and 11 underwent biventricular repair. After biventricular repair, 2 patients died, and 1 patient developed hemodynamic failure. As a result, only 8 patients were alive and in good condition. In patients who underwent LV rehabilitation, LV end-diastolic/end-systolic volume index, and LV stroke volume index increased over time after LV rehabilitation (p=0.001, p=0.007, and p=0.009, respectively). The zlog-NT-proBNP levels were stable until biventricular repair, but significantly higher in patients who presented with hemodynamic failure following biventricular repair compared to patients who did not exhibit hemodynamic failure. ConclusionsIn patients with borderline left heart hypoplasia, LV rehabilitation procedure promoted an increase in LV volume and contributed to establishing a biventricular circulation. The short-term results of this strategy are satisfactory, but further studies are essential to determine the long-term outcomes.

Pulmonary Overcirculation Requiring Surgical and Pulmonary Flow Restrictor Device Intervention in Critical Coarctation of the Aorta-A Case Series.

The use of prostaglandin infusion to maintain patency of the ductus arteriosus in patients with critical coarctation of the aorta (CoA) to support systemic circulation is the standard of care. However, pulmonary overcirculation resulting from a patent ductus arteriosus in patients with critical CoA is not well described in the literature. We report two cases of critical CoA that required invasive measures to control pulmonary blood flow before surgical repair of the CoA. Both patients had signs of decreased oxygen delivery, hyperlactatemia, and systemic to pulmonary flow via the ductus arteriosus. One patient required surgical pulmonary artery banding and the second patient underwent pulmonary flow restrictor device placement for the control of pulmonary blood flow. A rapid improvement in oxygen delivery and normalization of lactate levels were observed after control of pulmonary overcirculation. Both patients underwent successful surgical repair of the coarctation A and were discharged home.

Practice variation using the hybrid stage I procedure in congenital heart disease: Results from a national survey

ObjectivesHybrid stage I palliation has been used in many clinical scenarios including initial palliation in single ventricle heart disease, a bridge to biventricular repair, a bridge to transplant, and as a destination therapy. There is considerable hybrid stage I palliation practice variation, which we aimed to better understand in this study. MethodsSurvey-based assessment of practice variation related to hybrid stage I palliation was sent to congenital heart centers across the United States and Canada. ResultsOf the 106 centers surveyed, responses were received from 54 centers (50.9%). Of respondents, 45 centers perform hybrid stage I palliation. Centers most commonly (97.7%) perform hybrid stage I palliation on “high-risk” patients with single ventricle heart disease. Regarding the technical aspects of hybrid stage I palliation, most centers (95.3%) accomplish restrictive pulmonary blood flow using pulmonary artery bands and primarily use changes in oxygen saturation (34.1%) to identify appropriate restriction. Ductal stents are most often used (67.4%) to maintain ductal patency. Only 10 centers (23.3%) routinely enlarge the atrial septal defect. Indications for atrial septal defect intervention varied widely. Most centers (71.9%) discharge patients home to follow with a formal “interstage” program. ConclusionsThere is significant variation in practice patterns for hybrid stage I palliation indications, technical aspects, and postoperative care. Therefore, generalizability of single-center studies on outcomes after hybrid stage I palliation is limited. Future multicenter studies are needed to best delineate which patients benefit most from hybrid stage I palliation and to further define optimal approaches to caring for these patients.

Rat Model of Right-Sided Cardiac Remodeling and Arrhythmia using Pulmonary Artery Banding.

Clinical conditions, including chronic obstructive pulmonary disease or pulmonary arterial hypertension (PAH), can lead to chronic right ventricle pressure overload and progressive right heart failure (RHF). RHF can be identified by right-sided cardiac hypertrophy and dilation associated with abnormal myocardial function affecting the RV and the right atrium (RA). We recently demonstrated that severe RHF is accompanied by an increased risk of atrial inflammation, atrial fibrosis, and atrial fibrillation (AF), the most common type of cardiac arrhythmia (CA). Recent studies have shown that RV and RA inflammation plays an important role in the arrhythmogenesis of CA, including AF. However, the impact of inflammation in the development of CA and AF in RHF is poorly described. Experimental models of RHF are required to better understand the association between right-sided myocardial inflammation and CA. The rat model of monocrotaline (MCT)-induced pulmonary hypertension (PH) is well-established to provoke RHF. However, MCT triggers severe pneumo-toxicity and pulmonary inflammation. Hence, MCT-induced RHF does not help to distinguish whether the subsequent myocardial inflammation originates from the RHF per se or circulating inflammatory signals secreted by the injured lung. In this article, a mechanical method involving pulmonary artery trunk banding (PAB) was used to provoke right-sided cardiac arrhythmogenesis. The PAB consists of performing a permanent suture of the pulmonary artery trunk for 3 weeks. Such an approach generates increased right-sided pressure overload. At D21 post-PAB, the suture results in hypertrophied, dilated, and inflamed RV and RA. The PAB-induced RHF is also accompanied by vulnerability to ventricular and atrial arrhythmias, including AF.

Pulmonary artery banding in infants and young children with end-stage left ventricular dilated cardiomyopathy-Cohort Study.

Dilated cardiomyopathy (DCM) is the most common cardiomyopathy and 40-50% patients may die or need heart transplant in 5 years after diagnosis. Although heart transplantation being the most effective life-saving option of end-stage DCM, scarcity of donors and series of complications prevent many patients from receiving timely treatment. Pulmonary artery banding (PAB) is recently described as an alternative strategy for end-stage DCM, with low left ventricular function (LVEF) but preserved right ventricular function, may potentially restore heart function and delay the need for heart transplantation, but current clinical evidence is still insufficient. On the other hand, the medication treatment of DCM in pediatric patients is mostly based on the experience of adults. It remains unclear whether PAB combing medication treatment could benefit infants and young children patients. The aim of this study was to assess the short-term efficacy of PAB combined with medication therapy in infants and young children with end stage DCM, comparing with medication therapy alone. This is a retrospective analysis of 18 consecutive pediatric patients aged ranging from 1 month to 44 months old who diagnosed with end-stage DCM (LVEF30%) with preserved right ventricular function between 2019 and 2023 in our hospital. All patients had been treated with conventional medications for two months. Then they were divided in two groups: PAB surgery group (6/18), and non-surgery group (12/18). Regardless of whether surgery was performed, both groups continued to receive medication treatment. Recovery of ventricular function was primary endpoints. Secondary endpoints included 180-day mortality and severe heart failure (LVEF≤30%). We found there were no differences in age, weight, height, BMI, renal function, liver function, pulmonary hypertension, tricuspid valve regurgitation, mitral valve regurgitation and genetic abnormalities between those with and without PAB surgery. Comparing with non-surgery group, 5 patients in surgery group regain the normal cardiac ejection fraction (LVEF≥50%) (5/6, 83.3% vs. 4/12, 33.3%, P=0.131). A total of 3 patients had sudden death in non-surgery group, and there was no death in surgery group (P=0.180). 5 patients (5/12, 41.7%) still remain the low heart failure (LVEF≤40%) after 6 months of enrollment only given medical therapy, and none of patients present with LVEF≤40% in PAB surgery group (0/6, 0% vs. 8/12, 67.7%, P=0.034). Pulmonary artery banding is safe and effective in infants and young children with end-stage DCM with preserved right ventricular function. Combined with conventional heart failure medication therapy, it may provide short-term benefits post-operatively, decrease the cardiogenic shock, and act as a bridge to recovery and potentially reduce the need for heart transplantation. Long-term effects remain further observation, and larger randomized controlled trials would be more persuasive in validating its efficacy.

Short and Mid-term Outcomes of Ductal Graft with Bilateral Pulmonary Banding in Hypoplastic Left Heart Syndrome and Variants.

This study evaluates a novel surgical technique inspired by the hybrid Norwood procedure, which involves ductal graft placement and bilateral pulmonary artery banding. This technique is designed to avoid the high-risk classical Norwood stage 1 operation and to avoid the need for first stage invasive catheter interventions and interstage catheter interventions when ductal stent placement is not feasible in developing countries with limited resources. Between June 2015 and December 2022, 14 patients with hypoplastic left heart syndrome and variants were treated using this procedure at our center. Polytetrafluoroethylene graft was used for ductal graft procedure and polytetrafluoroethylene bands were used for bilateral pulmonary banding. Atrial septectomy was done selectively. Patients with adequate left heart growth underwent biventricular repair and pulmonary debanding. Patients without left heart growth underwent cavopulmonary anastomosis or necessary intermediate surgical revisions. Seven patients out of 14 reached the second stage. Two received biventricular repair, three underwent bidirectional cavopulmonary anastomosis, and two required repeat palliations other than bidirectional cavopulmonary anastomosis. Modifications of the Norwood procedure is an ongoing process due to the complex nature of hypoplastic left heart syndrome and variants. As experience grows, the mortality associated with ductal graft and bilateral pulmonary banding procedure may decrease, making this technique an alternative for centers where classical Norwood operation or hybrid palliation is not possible, especially in developing countries with limited resources. We might predict promising outcomes, especially for patients with hypoplastic left heart complex where biventricular repair is expected.

Inhibition of MRTF-A Ameliorates Pathological Remodeling of the Pressure-loaded Right Ventricle.

Right ventricular (RV) fibrosis is associated with RV dysfunction in a variety of RV pressure-loading conditions where RV mechanical stress is increased, but the underlying mechanisms driving RV fibrosis are incompletely understood. In pulmonary and cardiovascular diseases characterized by elevated mechanical stress and transforming growth factor - beta-1 (TGF-β1) signaling, myocardin-related transcription factor A (MRTF-A) is a mechanosensitive protein critical to driving myofibroblast transition and fibrosis. Here we investigated whether MRTF-A inhibition improves RV pro-fibrotic remodeling and function in response to a pulmonary artery banding (PAB) model of RV pressure-loading. Rats were assigned into either 1) sham or 2) PAB groups. MRTF-A inhibitor CCG-1423 was administered daily at 0.75mg/kg in a subset of PAB animals. Echocardiography and pressure-volume hemodynamics were obtained at a terminal experiment 6-weeks later. RV myocardial samples were analyzed for fibrosis, cardiomyocyte hypertrophy, and pro-fibrotic signaling. MRTF-A inhibition slightly reduced systolic dysfunction in PAB rats reflected by increased lateral tricuspid annulus peak systolic velocity, while diastolic function parameters were not significantly improved. RV remodeling was attenuated in PAB rats with MRTF-A inhibition, displaying reduced fibrosis. This was accompanied with a reduction in PAB-induced upregulation of yes-associated protein (YAP) and its paralog transcriptional co-activator with PDZ-binding motif (TAZ). We also confirmed using a second-generation MRTF-A inhibitor CCG-203971 that MRTF-A is critical in driving RV fibroblast expression of TAZ and markers of myofibroblast transition in response to TGF-β1 stress and RhoA activation. These studies identify RhoA, MRTF-A, and YAP/TAZ as interconnected regulators of pro-fibrotic signaling in RV pressure-loading, and as potential targets to improve RV pro-fibrotic remodeling.

Pulmonary Artery Banding and Arch Repair vs Norwood for Unbalanced Atrioventricular Canal Defect

BackgroundThe outcomes of single-ventricle palliation in unbalanced atrioventricular canal defect with coarctation of aorta (uAVC+CoA) have not been well studied. Systemic ventricle outflow tract obstruction has a propensity to develop in these patients after aortic arch repair with pulmonary artery banding (arch-PAB), which may adversely affect survival and Fontan candidacy. MethodsA retrospective review was performed of patients who underwent single-ventricle palliation for uAVC+CoA from 2000 to 2022. Patients were divided into 2 groups based on initial palliation: (1) arch-PAB and (2) Norwood procedure. Demographic and clinical characteristics were analyzed and compared along with survival data. ResultsStage 1 palliation for uAVC+CoA was performed in 41 patients. Arch-PAB was performed in 14 infants and Norwood in 27 infants. Arch-PAB patients had more chromosomal abnormalities (28.6 vs 7.4%, P < .009) and less severe systemic ventricle outflow tract obstruction on baseline echocardiogram (0.0 vs 70.4%, P < .001). Survival to stage 3 palliation was lower for the arch-PAB group (28.6% vs 66.6%, P = .02). Arch-PAB remained a significant risk factor for mortality (hazard ratio, 2.93; 95% CI, 1.05-8.53; P = .04) after adjusting for chromosomal abnormalities and atrioventricular valve regurgitation. After arch-PAB, systemic ventricle outflow tract obstruction was diagnosed in 13 of 14 patients. Echocardiography underestimated the degree of outflow tract obstruction in 10 of 13 arch-PAB patients. ConclusionsArch-PAB has worse outcomes than Norwood for uAVC+CoA. Systemic ventricle outflow tract obstruction develops in almost all patients after arch-PAB. Outflow tract obstruction is underestimated by the echocardiogram and requires a high index of suspicion, along with advanced imaging, to ensure timely diagnosis and management.

Abstract Tu051: ROR2 Drives Right Ventricular Failure Via Proteostatic Imbalances

Background: No therapies exist to treat right ventricular failure (RVF), in part because RVF molecular drivers have been incompletely studied. We recently identified that the developmentally restricted noncanonical WNT receptor ROR2 is re-expressed in a severity-dependent manner in human RVF. Here we test in mice if, and how, the re-expression of Ror2 causes RVF. Methods/Results: We find in neonatal rat ventricular myocytes (NRVMs) that Ror2 overexpression (Ror2 OE ) both activates protein translation and reduces Hspa1a/b mRNA and Hsp70 protein, resulting in increased protein turnover, fragmented sarcomeres, intercalated disc disruption, reduced cell major axis, impairment of contractile and relaxation kinetics, and ectopy. Ror2 knockdown (Ror2 KD ) results in opposing phenotypes. Hsp70 overexpression or proteasome inhibition rescues many of the Ror2 OE phenotypes, demonstrating their causal involvement. NRVM proteomic analysis indicates that Ror2 OE activates an ERK/p90RSK/Eef2 pathway that is known to regulate translation extension. In vivo, cardiac Ror2 OE in mice causes RV dilation and dysfunction, intercalated disc disruption, reduced Hspa1b (encoding for Hsp70), proteasome activation, and reduced cardiomyocyte ubiquitin staining. The mouse pulmonary artery banding (PAB) model of RVF reveals similar Ror2 induction and proteasome activation. Ror2 KD by AAV9 in PAB reduces RV dilation and improves RV systolic and diastolic function. Finally, in cardiac samples from human RVF, we find evidence for a similar ROR2-responsive proteostatic imbalance with increased proteasome activity and ubiquitin as well as markers of increased ERK and p90RSK. Conclusions: ROR2 is induced in human and mouse RVF, and mechanistic studies in NRVMs and mice show that the induction of ROR2 causes RVF by disrupting the proteostatic balance of translation, folding, and turnover. Knockdown or suppression of ROR2 may serve as a novel RVF therapeutic target.

Pulmonary artery banding to treat end-stage heart failure in infants and young children: A multicenter study

BackgroundConventional treatment options for end-stage heart failure (ESHF) in children include heart transplantation (HT) and ventricular assist device (VAD), both with significant drawbacks in the pediatric population. Pulmonary artery banding (PAB) strategy embedded in a protective cardiovascular drug regime has been effectively used for functional cardiac regeneration and as a bridge to HT in pediatric ESHF.We herein describe the early and mid-term clinical outcomes from a multicenter international experience. MethodsThis is a multicenter retrospective study including children admitted for ESHF caused by dilated cardiomyopathy of any etiology, who were treated with PAB. The primary outcome was the freedom from death/VAD/HT. Data are summarized as median (interquartile range) and count and percentages. Results31 patients (median age 210 days [131-357]) with ESHF underwent PAB in 5 centers. PEDIMACS score was I-III in 90%; 15 patients were intubated preoperatively. Preoperative left ventricular (LV) ejection fraction was <30% in 68%, with LV dilation in all cases. Postoperatively, median PAB gradient was 29 mmHg (23-34), and complications occurred in 14 patients (45%), with 4 (13%) early deaths. Twenty-seven patients were successfully discharged home on cardiac protective medical therapy. At a median follow-up of 2.9 years, there were 1 late death and 3 HTs. Freedom from death/VAD/HT was 77.3% (95% confidence interval [CI]=58-88.4%), 77.3% (95%CI=58-88.4%), and 73.2% (95%CI=53.2-85.5%) at 6 months, 1 year, and 2 years of follow-up, respectively. All 23 survivors with a native heart had gradual normalization of LV function and dimensions. ConclusionsPAB can be an effective procedure to treat ESHF in selected infants, as an innovative conservative strategy for bridging to transplant or recovery.

Echocardiographic Predictors of Readiness for Double Switch Operation and Postoperative Ejection Fraction in Patients With Congenitally Corrected Transposition of the Great Arteries Undergoing Left Ventricular Retraining

In patients with congenitally corrected transposition of the great arteries (ccTGA), assessment of readiness for the double switch operation (DSO) after pulmonary arterial band (PAB) placement involves cardiac magnetic resonance imaging (cMRI) to measure left ventricular ejection fraction (LVEF) and mass and cardiac catheterization (catheterization) to assess the ratio of left ventricular to right ventricular pressure (LV:RVp). The aims of this study were to describe the relationships between echocardiographic and catheterization and cMRI measures of readiness for DSO and to develop risk factors for left ventricular (LV) dysfunction after DSO on the basis of echocardiographic measures of ventricular-arterial coupling (VAC). Patients with ccTGA undergoing LV retraining at a DSO referral center were reviewed. LVEF measured by echocardiography was compared with that measured by cMRI, and LV:RVp measured by echocardiography was compared with that measured by catheterization using Bland-Altman analysis. The relationship between preoperative VAC markers and postoperative echocardiography was analyzed using ventricular end-systolic elastance (EES) and a novel marker consisting of the product of LVEF and LV:RVp (EFPR). Thirty-one patients with 56 evaluations for DSO were included, 24 of whom underwent DSO. Echocardiographic LVEF correlated well with cMRI LVEF (r=0.79), and Bland-Altman analysis slightly overestimated cMRI LVEF (mean difference,+3%). Echocardiographic LVEF had a moderate ability to identify normal cMRI LVEF (area under the curve, 0.80) and at an optimal cut point of echocardiographic LVEF threshold of 61%, there was 71% sensitivity and 76% specificity to detect cMRI LVEF≥55%. Echocardiographic LV:RVp correlated well with LV/RVp by catheterization (r=0.77) and slightly underestimated the catheterization value (mean difference, -0.11). Echocardiographic LV:RVp had a good ability to identify adequate LV:RVp by catheterization (area under the curve, 0.95) and at an optimal echocardiography cut point of 0.75 had 100% sensitivity and 85% specificity to detect a catheterization LV:RVp >0.9. Echocardiography-based criteria for DSO readiness (echocardiographic LVEF of 61% and LV:RVp of 0.75) demonstrated specificity of 97% and positive predictive value of 96% for published criteria of DSO readiness (cMRI LVEF of 55% and catheterization LV:RVp of 0.9). EES and EFPR correlated with post-DSO LVEF (ρ=0.72 and ρ=0.60, respectively). EFPR of 0.51 demonstrated 78% sensitivity and 100% specificity for post-DSO LV dysfunction (LVEF<55%). Age at first PAB also strongly correlated with post-DSO LVEF (ρ=0.75). No patient with first PAB at <1year of age exhibited post-DSO LV dysfunction. Echocardiographic measures of LVEF and LV:RVp are reliable indicators of reference standard modalities and can guide management during retraining. The preoperative VAC markers EES and EFPR may be useful markers of post-DSO LV dysfunction. Values of echocardiographic LV:RVp >0.75 are likely to meet pressure-generation criteria for DSO and should be considered for referral to catheterization and cMRI evaluation for DSO. PAB placement before 1year of life may optimize LV outcomes in patients considered for DSO.

Impact of Right Ventricular Pressure Overload on Myocardial Stiffness Assessed by Natural Wave Imaging.

Right ventricular (RV) hemodynamic performance determines the prognosis of patients with RV pressure overload. Using ultrafast ultrasound, natural wave velocity (NWV) induced by cardiac valve closure was proposed as a new surrogate to quantify myocardial stiffness. This study aimed to assess RV NWV in rodent models and children with RV pressure overload vs control subjects and to correlate NWV with RV hemodynamic parameters. Six-week-old rats were randomized to pulmonary artery banding (n=6), Sugen hypoxia-induced pulmonary arterial hypertension (n=7), or sham (n=6) groups. They underwent natural wave imaging, echocardiography, and hemodynamic assessment at baseline and 6weeks postoperatively. The authors analyzed NWV after tricuspid and after pulmonary valve closure (TVC and PVC, respectively). Conductance catheters were used to generate pressure-volume loops. In parallel, the authors prospectively recruited 14 children (7 RV pressure overload; 7 age-matched control subjects) and compared RV NWV with echocardiographic and invasive hemodynamic parameters. NWV significantly increased in RV pressure overload rat models (4.99 ± 0.27m/s after TVC and 5.03 ± 0.32m/s after PVC in pulmonary artery banding at 6weeks; 4.89 ± 0.26m/s after TVC and 4.84 ± 0.30m/s after PVC in Sugen hypoxia at 6weeks) compared with control subjects (2.83 ± 0.15m/s after TVC and 2.72 ± 0.34m/s after PVC). NWV after TVC correlated with both systolic and diastolic parameters including RV dP/dtmax (r=0.75; P< 0.005) and RV Ees (r=0.81; P< 0.005). NWV after PVC correlated with both diastolic and systolic parameters and notably with RV end-diastolic pressure (r=0.65; P< 0.01). In children, NWV after both right valves closure in RV pressure overload were higher than in healthy volunteers (P< 0.01). NWV after PVC correlated with RV E/E' (r=0.81; P=0.008) and with RV chamber stiffness (r=0.97; P=0.03). Both RV early-systolic and early-diastolic myocardial stiffness show significant increase in response to pressure overload. Based on physiology and our observations, early-systolic myocardial stiffness may reflect contractility, whereas early-diastolic myocardial stiffness might be indicative of diastolic function.