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Assessment of the right ventricular outflow tract and pulmonary arteries (RVOT) for percutaneous pulmonary valve implantation (PPVI) uses discrete measurements (diameters and lengths) from medical images. This multi-centre study identified the 3D RVOT shape features prevalent in patients late after surgical repair of congenital heart disease (CHD). A 3D RVOT statistical shape model (SSM) was computed from 81 retrospectively selected CHD patients (14.7 ± 6.8 years) who required pulmonary valve replacement late after surgical repair. A principal component analysis identified prevalent shape features (modes) within the population which were compared with standard geometric measurements (diameter, length and surface area) and between sub-groups of diagnosis, RVOT type and dysfunction. Shape mode 1 and 2 represented RVOT size and curvature and tapering and length, respectively. Shape modes 3–5 related to branch pulmonary artery calibre, conical vs. bulbous RVOTs and RVOT curvature, respectively. Tetralogy of Fallot, transannular patch type and regurgitant RVOTs were larger and straighter while conduit and stenotic types were longer and more cylindrical than other subgroups. This SSM analysed the main 3D shape features present in a population of RVOTs, exploiting the wide 3D anatomical information provided by routine imaging. This morphological information may have implications for PPVI patient selection and device design.

Abstract Low blood flow through the fetal left heart is often conjectured as an etiology for hypoplastic left heart syndrome (HLHS). To investigate if a decrease in left heart flow results in growth failure, we generate left ventricular inflow obstruction (LVIO) in mid-gestation fetal lambs by implanting coils in their left atrium using an ultrasound-guided percutaneous technique. Significant LVIO recapitulates important clinical features of HLHS: decreased antegrade aortic valve flow, compensatory retrograde perfusion of the brain and ascending aorta (AAo) from the arterial duct, severe left heart hypoplasia, a non-apex forming LV, and a thickened endocardial layer. The hypoplastic AAo have miRNA-gene pairs annotating to cell proliferation that are inversely differentially expressed by bulk RNA-seq. Single-nucleus RNA-seq of the hypoplastic LV myocardium shows an increase in fibroblasts with a reciprocal decrease in cardiomyocyte nuclei proportions. Fibroblasts, cardiomyocytes and endothelial cells from hypoplastic myocardium have increased expression of extracellular matrix component or fibrosis genes with dysregulated fibroblast growth factor signaling. Hence, a severe sustained ( ~ 1/3 gestation) reduction in fetal left heart flow is sufficient to cause left heart hypoplasia. This is accompanied by changes in cellular composition and gene expression consistent with a pro-fibrotic environment and aberrant induction of mesenchymal programs.

In hypoplastic left heart syndrome (HLHS), the mechanisms leading to left heart hypoplasia and their associated fetal abnormalities are largely unknown. Current animal models have limited utility in resolving these questions as they either do not fully reproduce the cardiac phenotype, do not survive to term and/or have very low disease penetrance. Here, we report the development of a surgically induced mouse model of HLHS that overcomes these limitations. Briefly, we microinjected the fetal left atrium of embryonic day (E)14.5 mice with an embolizing agent under high-frequency ultrasound guidance, which partially blocks blood flow into the left heart and induces hypoplasia. At term (E18.5), all positively embolized mice exhibit retrograde aortic arch flow, non-apex-forming left ventricles and hypoplastic ascending aortas. We thus report the development of the first mouse model of isolated HLHS with a fully penetrant cardiac phenotype and survival to term. Our method allows for the interrogation of previously intractable questions, such as determining the mechanisms of cardiac hypoplasia and fetal abnormalities observed in HLHS, as well as testing of mechanism-based therapies, which are urgently lacking.

Hypoplastic left heart syndrome (HLHS) is a life-threatening congenital heart disease that is characterized by severe underdevelopment of left heart structures. Currently, there is no cure, and affected individuals require surgical palliation or cardiac transplantation to survive. Despite these resource-intensive measures, only about half of individuals reach adulthood, often with significant comorbidities such as liver disease and neurodevelopmental disorders. A major barrier in developing effective treatments is that the etiology of HLHS is largely unknown. Here, we discuss how intracardiac blood flow disturbances are an important causal factor in the pathogenesis of impaired left heart growth. Specifically, we highlight results from a recently developed mouse model in which surgically reducing blood flow through the mitral valve after cardiogenesis led to the development of HLHS. In addition, we discuss the role of interventional procedures that are based on improving blood flow through the left heart, such as fetal aortic valvuloplasty. Lastly, using the surgically-induced mouse model, we suggest investigations that can be undertaken to identify the currently unknown biological pathways in left heart growth failure and their associated therapeutic targets.

Radiofrequency (RF) assisted perforation of the atrial septum was performed successfully in three infants using a 0.035΂ RF wire deployed through a Williams right posterior catheter. Balloon atrial septoplasty was performed over the 0.035΂ RF wire in two of them, shortening the procedural time.

Neoaortic root dilation is a common phenomenon after the Norwood procedure, but the real incidence and its natural history are unclear. Regular surveillance in these patients after the operation is necessary. Herein, we present an 11-year-old boy born with tricuspid atresia, a discordant ventriculo-arterial connection and a hypoplastic aortic arch, who was palliated initially with a hybrid stage I procedure involving a reversed Blalock-Taussig shunt, followed by comprehensive stage II and then, an extra-cardiac fenestrated Fontan operation. The patient developed an aortic root aneurysm and severe aortic regurgitation. He was electively taken into the operating room, where cardiopulmonary bypass was established through a peripheral cannulation of the femoral vessels due to the high risk nature of the reoperation. A mechanical Bentall procedure was performed without residual lesions and the native ascending aorta was anastomosed as a single coronary button to the anterior wall of the graft., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Recent genome-wide studies of rare genetic variants have begun to implicate novel mechanisms for tetralogy of Fallot (TOF), a severe congenital heart defect (CHD). To provide statistical support for case-only data without parental genomes, we re-analyzed genome sequences of 231 individuals with TOF ( n = 175) or related CHD. We adapted a burden test originally developed for de novo variants to assess ultra-rare variant burden in individual genes, and in gene-sets corresponding to functional pathways and mouse phenotypes, accounting for highly correlated gene-sets and for multiple testing. For truncating variants, the gene burden test confirmed significant burden in FLT4 (Bonferroni corrected p -value < 0.01). For missense variants, burden in NOTCH1 achieved genome-wide significance only when restricted to constrained genes (i.e., under negative selection, Bonferroni corrected p -value = 0.004), and showed enrichment for variants affecting the extracellular domain, especially those disrupting cysteine residues forming disulfide bonds (OR = 39.8 vs. gnomAD). Individuals with NOTCH1 ultra-rare missense variants, all with TOF, were enriched for positive family history of CHD. Other genes not previously implicated in CHD had more modest statistical support in gene burden tests. Gene-set burden tests for truncating variants identified a cluster of pathways corresponding to VEGF signaling ( FDR = 0%), and of mouse phenotypes corresponding to abnormal vasculature ( FDR = 0.8%); these suggested additional candidate genes not previously identified (e.g., WNT5A and ZFAND5 ). Results for the most promising genes were driven by the TOF subset of the cohort. The findings support the importance of ultra-rare variants disrupting genes involved in VEGF and NOTCH signaling in the genetic architecture of TOF, accounting for 11-14% of individuals in the TOF cohort. These proof-of-principle data indicate that this statistical methodology could assist in analyzing case-only sequencing data in which ultra-rare variants, whether de novo or inherited, contribute to the genetic etiopathogenesis of a complex disorder., (Copyright © 2020 Manshaei, Merico, Reuter, Engchuan, Mojarad, Chaturvedi, Heung, Pellecchia, Zarrei, Nalpathamkalam, Khan, Okello, Liston, Curtis, Yuen, Marshall, Jobling, Oechslin, Wald, Silversides, Scherer, Kim and Bassett.)

Objective: To investigate the regional flow distribution in patients with Fontan circulation by using magnetic resonance imaging (MRI)., Materials and Methods: We identified 39 children (18 females and 21 males; mean age, 9.3 years; age range, 3.3-17.0 years) with Fontan circulation in whom flow volumes across the thoracic and abdominal arteries and veins were measured by using MRI. The patients were divided into three groups: fenestrated Fontan circulation group with MRI performed under general anesthesia (GA) (Group 1, 15 patients; average age, 5.9 years), completed Fontan circulation group with MRI performed under GA (Group 2, 6 patients; average age, 8.7 years), and completed Fontan circulation group with MRI performed without GA (Group 3, 18 patients; average age, 12.5 years). The patient data were compared with the reference ranges in healthy controls., Results: In comparison with the controls, Group 1 showed normal cardiac output (3.92 ± 0.40 vs. 3.72 ± 0.69 L/min/m², p = 0.30), while Group 3 showed decreased cardiac output (3.24 ± 0.71 vs. 3.96 ± 0.64 L/min/m², p = 0.003). Groups 1 and 3 showed reduced abdominal flow (1.21 ± 0.28 vs. 2.37 ± 0.45 L/min/m², p < 0.001 and 1.89 ± 0.39 vs. 2.64 ± 0.38 L/min/m², p < 0.001, respectively), which was mainly due to the diversion of the cardiac output to the aortopulmonary collaterals in Group 1 and the reduced cardiac output in Group 3. Superior mesenteric and portal venous flows were more severely reduced in Group 3 than in Group 1 (ratios between the flow volumes of the patients and healthy controls was 0.26 and 0.37 in Group 3 and 0.63 and 0.53 in Group 1, respectively). Hepatic arterial flow was decreased in Group 1 (0.11 ± 0.22 vs. 0.34 ± 0.38 L/min/m², p = 0.04) and markedly increased in Group 3 (0.38 ± 0.22 vs. -0.08 ± 0.29 L/min/m², p < 0.0001). Group 2 showed a mixture of the patterns seen in Groups 1 and 3., Conclusion: Fontan circulation is associated with reduced abdominal flow, which can be attributed to reduced cardiac output and portal venous return in completed Fontan circulation, and diversion of the cardiac output to the aortopulmonary collaterals in fenestrated Fontan circulation., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2019 The Korean Society of Radiology.)

Objectives: Mortality associated with the modified Blalock-Taussig shunt (MBTS) remains high despite advanced perioperative management. This study was formulated to provide data on (1) current indications, (2) outcomes, and (3) factors affecting mortality and morbidity., Design: A retrospective single center chart review identified 95 children (excluding hypoplastic left heart lesions) requiring a MBTS. Mortality and major morbidity were analyzed using the Kaplan Meier method and risk factor analysis using Cox's proportional hazard regression., Results: Median age was 8 (0-126) days, weight 3.1(1.7-5.4) kg. Seventy-three percent were neonates, 58% duct dependent and 73% had single ventricle physiology. Ninety-seven percent had a sternotomy approach for shunt placement with 70% receiving a 3.5 mm graft. Mean graft index (shunt cross sectional area [mm 2 ]/BSA [m 2 ]) was 44.39 ± 8.04 and shunt size (mm) to body weight (kg) ratio 1.1 ± 0.2. Hospital mortality was 12%, with an interval mortality of 6%. Shunt thrombosis/stenosis occurred in 23% and pulmonary over circulation in 30%, while shunt reoperation was required in 12% and catheter intervention in 8% of the cohort. At 1-year, survival was 82.0% (95% CI [72.7%, 88.4%]), and survival free of major morbidity 61.4% (95% CI [50.7%, 70.5%]). Duct dependency predisposed to mortality (P = .01, HR 6.74 [1.54, 29.53]) and composite outcome (mortality and major morbidity) (P = .04, HR 2.15, CI [1.036, 4.466]) and higher graft index to mortality (P = .005, HR 1.07 [1.02, 1.12])., Conclusions: The commonest indication for a MBTS in the current era was single ventricle palliation. Morbidity and mortality was considerable, partly explained by the higher at risk population. Alternative methods to maintain pulmonary blood flow in place of a MBTS requires further investigation., (© 2017 Wiley Periodicals, Inc.)

Background: Percutaneous pulmonary valve implantation (PPVI) is a safe, less invasive alternative to surgical valve replacement for the congenital heart disease patient with right ventricular (RV) outflow tract dysfunction. The aim of this study was to determine whether reverse RV remodeling after PPVI was persistent in the longer term and whether timing of PPVI influenced outcomes., Methods and Results: Consecutive patients from the pediatric and adult congenital heart disease programs were enrolled. Cardiac MRI, echocardiography, metabolic exercise testing, chest radiography, and hemodynamics before intervention were compared with repeated follow-up measurements to assess changes over time. Fifty-one patients (including 23 patients <16 years old) were followed for a mean 4.5±1.9 (0.9-6.9) years after implantation, 59% of patients having available comparative cardiac MRI data. Freedom from any reintervention was 87% and 68% at 3 and 5 years, and freedom from surgery was 90% at 5 years. For every decade younger at implantation, there was an increase of 3.9%±1.0% in cardiac MRI left ventricular ejection fraction (P<0.001) and 2.4±0.9 mL/kg/min in maxVO2 (P=0.005) and a decrease of 0.7±0.2 cm in RV end-diastolic dimension (P<0.001) after intervention. Younger patients displayed an additional decline in the RV/left ventricular end-diastolic volume ratio (P=0.05) and trended toward improved RV ejection fraction in late follow-up (50%±7% versus 41%±12%, P=0.07)., Conclusions: This is the largest series to show that PPVI at a younger age yields incremental improvements in RV size and maximum oxygen consumption. Early valve implantation is associated with better RV function and should be considered in management planning for this population., (© 2015 American Heart Association, Inc.)

Objective: Retrograde aortic arch malperfusion after ductal stenting can be life-threatening after univentricular hybrid palliation. Arch perfusion can be maintained with a main pulmonary artery to innominate artery shunt placed during the stage I procedure: a "reverse Blalock-Taussig shunt.", Methods: A retrospective review of 37 infants who underwent hybrid palliation from January 2004 to March 2010 was performed. The infants were divided into 2 groups, those with (group I, n = 16) and those without (group II, n = 21) a reverse Blalock-Taussig shunt., Results: At the initial palliation, no differences were found in the demographics, systolic or diastolic pressures, or ventricular or atrioventricular valve function between the 2 groups. Group I had more infants with aortic atresia (P < .01) and smaller ascending aortas (P < .01). Before stage II, the retrograde aortic Doppler flow velocity increased in group I (P < .01) and was unchanged in group II. The reintervention rates before stage II were similar between the 2 groups. Before stage II, the ventricular end-diastolic pressure, left and right pulmonary artery pressures and diameters, and mixed venous and arterial saturations were similar between the 2 groups. The complication rates between the 2 groups were not significantly different, although a nonsignificant trend toward more neurologic complications was noted in group I. The Kaplan-Meier survival estimate at 1 year was similar between the 2 groups (63% for group I vs 71% for group II)., Conclusions: The presence of a reverse Blalock-Taussig shunt was not associated with more adverse events than those without. Gradual retrograde arch obstruction occurs commonly in palliated infants with aortic atresia. A reverse Blalock-Taussig shunt might play an important role to address the potential of retrograde obstruction, augmenting arch blood flow., (Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Ductal stenting plays a central role in hybrid palliation (with bilateral pulmonary artery [PA] banding) for hypoplastic left heart syndrome (HLHS). The "natural" history of ductal stent is relatively unknown., Methods: We retrospectively reviewed 37 neonates with HLHS or its variants who underwent hybrid palliation between January 2004 and March 2010., Results: Forty-nine ductal stents were deployed in 37 neonates. A single stent was implanted in 26, 2 in 10, and 3 in 1 neonate at the index procedure. There were 5 neonates (13.5%) who required reintervention on the stent with an additional implant; 4 stents were placed proximally (PA-end) and 1 on the aorta side. No infant required reintervention on the stent if the implant covered from the PA junction to beyond the aortic isthmus. There were 2 infants (5.4%) who developed retrograde arch obstruction. Of the cohort, 9 died before stage II, 1 had a bidirectional cavopulmonary shunt after conversion to a Norwood circulation, and 27 underwent comprehensive stage II. In 24 infants who did not require an additional stent, duct velocity increased during follow-up (p < 0.001). Stent position was altered distally in relation to the anterior border of the trachea with child growth., Conclusions: The stent should cover the full length of the duct from the PA junction to beyond the arch isthmus to reduce reintervention rates. Such stents tend to have progressive stenosis and move distally with child growth. However, lower body blood flow appears well maintained until the time of a comprehensive stage II repair., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: The goal of this study was to prospectively assess blood pressure (BP) and echocardiographic parameters to delineate the incidence and nature of the hypertension burden in this cohort., Background: Few data are available on the long-term outcomes of aortic stenting., Methods: Thirty-one patients with successfully stented coarctation during childhood (mean age 12.4 years) underwent 24-h ambulatory BP monitoring (ABPM), exercise BP measurement, and echocardiographic assessment., Results: Mean time after stent implantation was 5.3 ± 4 years. Hypertension was noted on one-off right-arm BP assessment in 3 patients (10%), but on the basis of the 24-h ABPM assessment in 14 patients (45%). Twenty-four of 31 patients (80%) had an abnormally elevated exercise BP response. Peak exercise BP correlated with left ventricular mass index (r = 0.51; p < 0.05), which was also significantly increased in the entire cohort (mean = 91.3 g/m(2); p < 0.05). In patients with significant somatic growth since implantation, the indexed diameter of the stent (to aortic diameter) had significantly decreased from the 48th percentile at the implantation to the 4th percentile during the study (p < 0.05). There was no difference in any parameter between patients with native or those with recurrent coarctation., Conclusions: Hypertension is endemic in patients with stented coarctation, irrespective of the absence of residual obstruction. Due to abnormal BP homeostasis, hypertension should be aggressively pursued by ABPM assessment and exercise stress testing in this population. Relative hypoplasia of the stented arch after somatic growth may contribute to this tendency and should provoke consideration of elective serial redilation of coarctation stents., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: Aortopulmonary collaterals are a frequent phenomenon in patients after bidirectional cavopulmonary connection. The aortopulmonary collateral flow volume can be quantified using cardiac magnetic resonance imaging. However, the significance of aortopulmonary collateral flow for the postoperative outcome after total cavopulmonary connection is unclear and was sought to be determined., Methods: The data from 33 patients were prospectively studied with cardiac magnetic resonance, echocardiography, and cardiac catheterization before the total cavopulmonary connection operation. The early postoperative outcomes after total cavopulmonary connection completion were recorded., Results: Aortopulmonary collateral flow was 1.59 L/min/m(2) ± 0.65 L/min/m(2) (range, 0.54 L/min/m(2)-3.34 L/min/m(2)), constituting 43% ± 13% (range, 12-87%) of pulmonary blood flow and 35% ± 12% (range, 11-62%) of the cardiac index, resulting in a pulmonary blood flow/systemic blood flow ratio of 1.06 ± 0.17 (range, 0.79-1.55). The aortopulmonary collateral flow correlated with pulmonary blood flow/systemic blood flow ratio (r = 0.69, P < .0001), oxygen saturation (r = 0.42, P = .018), and cardiac index (r = 0.53, P = .002). Of the 36 patients, 24 underwent fenestrated total cavopulmonary connection during the study period. The aortopulmonary collateral flow, relative to the cardiac index, correlated with the duration of hospital stay (r = 0.48, P = .02) and pleural drainage (r = 0.45, P = .03). Patients whose pleural drainage lasted 1 week or less had less aortopulmonary collateral flow before the Fontan operation than those with a longer period until chest tube removal (1.23 L/min/m(2) ± 0.38 L/min/m(2) vs 1.73 L/min/m(2) ± 0.76 L/min/m(2); P = .03). Compared with a contemporary group of total cavopulmonary connection patients with fenestration in their extracardiac conduit who were studied prospectively, with a similar protocol, the bidirectional cavopulmonary connection had a greater amount of aortopulmonary collateral flow (1.59 L/min/m(2) ± 0.65 L/min/m(2) vs 1.30 L/min/m(2) ± 0.57 L/min/m(2), P = .04)., Conclusions: Patients after bidirectional cavopulmonary connection routinely acquire a large amount of aortopulmonary collateral flow. The hemodynamic consequences of aortopulmonary collateral flow translate into adverse outcomes early after total cavopulmonary connection completion., (Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Titin is a muscle-specific protein found in cardiac and skeletal muscles which is responsible for restoring passive tension. Levels and functioning of titin have been shown to be affected by cardiac damage. Due to the inherent difficulty of measuring titin levels in vivo in a clinical setting, we aimed to develop an assay that could reliably measure fragments of degraded titin in serum and potentially be used in the assessment of cardiac muscle damage., Methods: A competitive ELISA was developed to specifically measure levels of the titin sequence 12670' NVTVEARLIK 12679', derived by the degradation of titin by matrix metalloproteinase (MMP)-12. Serum samples from 90 individuals were divided into 3 equally sized groups. One group had been diagnosed with acute myocardial infarction (AMI) while the remaining two were asymptomatic individuals either with CT-scan signs of coronary calcium (CT-plusCa) or without coronary calcium (CT-noCa)., Results: Mean geometric levels of the titin fragment in the CT-noCa group were 506.5 ng/ml (± 43.88). The CT-plusCa group showed 50.6% higher levels of the marker [763 ng/ml (± 90.14)] (P < 0.05). AMI patients showed 56.3% higher levels [792 ng/ml (± 149)] (P < 0.05)., Conclusions: The titin-12670 fragment is present in both individuals with undiagnosed and diagnosed CVD. The statistically significant increase in level of the marker in the AMI group is indicative that this neoepitope biomarker may be a useful serological marker in AMI.

Aims: Replacement of bioprosthetic valves in the right ventricular (RV) outflow tract (RVOT) is inevitable due to acquired valvar dysfunction. Percutaneous pulmonary valve implantation (PPVI) may result in acceptable clinical improvement avoiding surgical reintervention. To report outcomes of PPVI in dysfunctional surgically implanted bioprosthetic valves., Methods and Results: All children undergoing PPVI into a bioprosthetic pulmonary valve between October 2005 and February 2008 were reviewed. Acute haemodynamic changes were compared and an analysis of variance applied to assess changes in ventricular geometry and pressure over time. Fourteen children (seven males), median weight 57.8 kg and 14.7 years of age were identified, with an echocardiographic RVOT gradient of 59.6 +/- 26.8 mmHg and a pulmonary regurgitation (PR) grade of 3.6 +/- 0.8 (out of 4). Implantation was successful in all. Twenty-four hours after implantation, there was a significant improvement in RV pressure (RVP) (from 82.2 +/- 15.6 to 59.4 +/- 9.9 mmHg, P < 0.001) and degree of PR to 0.6 +/- 0.9 (P < 0.001). Mean hospital stay was 2.0 +/- 0.4 days. Freedom from reintervention was 92 and 89% at 1 and 2 years, respectively. Follow-up echocardiography (mean 12.9 +/- 9.8 months) revealed a further reduction in RVP (P < 0.001) and RVOT gradients (P < 0.001) and an increase in left ventricular end-diastolic volume (P= 0.01) and aortic valve annulus diameters (P < 0.001)., Conclusions: Percutaneous pulmonary valve implantation for RVOT dysfunction in a previously implanted prosthetic valve is feasible and safe. Short-term follow-up data are encouraging, yet longer-term information is required to determine if this form of palliation has a significant impact on management strategies.

Introduction: Pre-operative recognition of significant abnormalities of the coronary arteries is important in a variety of congenital cardiac conditions. Failure to diagnose anomalous origin of the coronary artery from the pulmonary artery during repair of other anomalies is important because reduction in pulmonary artery pressure will reduce myocardial perfusion pressure., Patients: We report two cases of the rare association of anomalous origin of the left coronary artery from the right pulmonary artery, aortic coarctation, and mitral stenosis., Conclusions: Definitive imaging of coronary artery anatomy by echocardiography or other modalities should form a routine part of diagnostic assessment in all congenital heart disease patients but particularly those with left heart obstruction.

Objectives: The aim of this study was to investigate physiological and clinical consequences of percutaneous pulmonary valve implantation (PPVI) in patients with chronic right ventricular outflow tract (RVOT) obstruction and volume overload., Background: The PPVI is a nonsurgical technique to address RVOT conduit dysfunction., Methods: Twenty-eight adolescents (median age 14.9 years; age range 10.9 to 19 years) underwent PPVI due to RVOT stenosis and/or pulmonary regurgitation (PR). Before and after PPVI echocardiographic and magnetic resonance imaging, cardiopulmonary exercise tests were obtained., Results: The RVOT gradient (p < 0.001) and right ventricular (RV) systolic pressure decreased (p < 0.001), acutely. Magnetic resonance imaging (median 6 months) documented reduction in RV end-diastolic (149 +/- 49 ml/m(2) vs. 114 +/- 35 ml/m(2), p < 0.005) volume, increases in left ventricular (LV) end-diastolic (p < 0.007) volume and cardiac output (RV: p < 0.04 and LV: p < 0.02), and reduced PR fraction (24 +/- 10% to 7 +/- 7%, p < 0.0001). Symptoms, aerobic exercise performance (maximal oxygen consumption: p < 0.0001) and ventilatory response to carbon dioxide production (p < 0.003) improved. After 24 months, echocardiography demonstrated the RV/systemic-pressure ratio, and RVOT peak pressure gradient reductions persisted, and PR was absent in 93% (n = 12 of 13) of the cohort. Freedom from surgery was 91%, 83%, and 83%, and freedom from transcatheter reintervention was 91%, 80%, and 80%, at 12, 24, and 36 months, respectively. There were no acute device-related complications, with stent fractures noted in 10.8%., Conclusions: Percutaneous pulmonary valve implantation is feasible and safe in the young with dysfunctional RVOT conduits. An improvement in symptoms, hemodynamic status, and objective findings of exercise performance occurs. Early follow-up demonstrates persistent improvement in ventricular parameters, PR, and objective exercise capacity., (Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Myosin binding protein-C (MyBP-C) is a poorly understood component of the thick filament in striated muscle sarcomeres. Its C terminus binds tightly to myosin, whereas the N terminus contains binding sites for myosin S2 and possibly for the thin filament. To study the role of the N-terminal domains of cardiac MyBP-C (cMyBP-C), we added human N-terminal peptide fragments to human and rodent skinned ventricular myocytes. At concentrations >10 micromol/L, the N-terminal C0C2 peptide activated force production in the absence of calcium (pCa 9). Force at the optimal concentration (80 micromol/L) of C0C2 was approximately 60% of that in maximal Ca2+ (pCa 4.5), but the rate constant of tension redevelopment (ktr) matched or exceeded (by up to 80%) that produced by Ca2+ alone. Experiments using different N-terminal peptides suggested that this activating effect of C0C2 resulted from binding by the pro/ala-rich C0-C1 linker region, rather than the terminal C0 domain. At a lower concentration (1 micromol/L), exogenous C0C2 strongly sensitized cardiac myofibrils to Ca2+ at a sarcomere length (SL) of 1.9 microm but had no significant effect at SL 2.3 microm. This differential effect caused the normal SL dependence of myofibrillar Ca2+ sensitivity to be reduced by 80% (mouse myocytes) or abolished (human myocytes) in 1 micromol/L C0C2. These results suggest that cMyBP-C provides a regulatory pathway by which the thick filament can influence the activation of the thin filament, separately from its regulation by Ca2+. Furthermore, the N-terminal region of cMyBP-C can influence the SL-tension (Frank-Starling) relationship in cardiac muscle.