Atsushi Tateishi

Intracoronary Autologous Cardiac Progenitor Cell Transfer in Patients With Hypoplastic Left Heart Syndrome The TICAP Prospective Phase 1 Controlled Trial

Rationale: Hypoplastic left heart syndrome (HLHS) remains a lethal congenital cardiac defect. Recent studies have suggested that intracoronary administration of autologous cardiosphere-derived cells (CDCs) may improve ventricular function. Objective: The aim of this study was to test whether intracoronary delivery of CDCs is feasible and safe in patients with hypoplastic left heart syndrome. Methods and Results: Between January 5, 2011, and January 16, 2012, 14 patients (1.8±1.5 years) were prospectively assigned to receive intracoronary infusion of autologous CDCs 33.4±8.1 days after staged procedures (n=7), followed by 7 controls with standard palliation alone. The primary end point was to assess the safety, and the secondary end point included the preliminary efficacy to verify the right ventricular ejection fraction improvements between baseline and 3 months. Manufacturing and intracoronary delivery of CDCs were feasible, and no serious adverse events were reported within the 18-month follow-up. Patients treated with CDCs showed right ventricular ejection fraction improvement from baseline to 3-month follow-up (46.9%±4.6% to 52.1%±2.4%; P=0.008). Compared with controls at 18 months, cardiac MRI analysis of CDC-treated patients showed a higher right ventricular ejection fraction (31.5%±6.8% versus 40.4%±7.6%; P=0.049), improved somatic growth (P=0.0005), reduced heart failure status (P=0.003), and lower incidence of coil occlusion for collaterals (P=0.007). Conclusions: Intracoronary infusion of autologous CDCs seems to be feasible and safe in children with hypoplastic left heart syndrome after staged surgery. Large phase 2 trials are warranted to examine the potential effects of cardiac function improvements and the long-term benefits of clinical outcomes. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01273857.

A Cell-permeable NFAT Inhibitor Peptide Prevents Pressure-Overload Cardiac Hypertrophy

The activation of the calcineurin–nuclear factor of activated T cells cascade during the development of pressure‐overload cardiac hypertrophy has been previously reported in a number of studies. In addition, numerous pharmacological studies involving calcineurin inhibitors such as FK506 and cyclosporine A have now demonstrated that these agents can prevent such hypertrophic responses in the heart. However, little is known regarding the roles of the calcineurin downstream effecter – nuclear factor of activated T cells. Our present study has further examined the roles of nuclear factor of activated T cells in pressure‐overload cardiac hypertrophy by employing a recently developed cell‐permeable nuclear factor of activated T cells inhibitor peptide. Rat hearts were subjected to pressure overload attributable by 4 weeks of aortic banding, and then treated with this cell‐permeable nuclear factor of activated T cells inhibitor peptide and a control peptide. Treatment with the inhibitor was found to significantly decrease the heart weight/body weight ratio, the size of cardiac myocytes, and the serum brain natriuretic peptide and atrial natriuretic peptide levels. These results suggest that nuclear factor of activated T cells functions in a key role in the development of cardiac hypertrophy during pressure overload. Inhibition of nuclear factor of activated T cells by a specific inhibitor peptide is a suitable method for characterization of the molecular mechanisms underlying cardiac hypertrophy as well as in the search for new promising therapies for disease.

Effect of inhibition of glycogen synthase kinase-3 on cardiac hypertrophy during acute pressure overload.

ObjectiveA large number of diverse signaling molecules in cell and animal models participate in the stimulus-response pathway through which the hypertrophic growth of the myocardium is controlled. However, the mechanisms of signaling pathway including the influence of lithium, which is known as an inhibitor of glycogen synthase kinase-3β, in pressure overload hypertrophy remain unclear. The aim of our study was to determine whether glycogen synthase kinase-3β inhibition by lithium has acute effects on the myocyte growth mechanism in a pressure overload rat model.MethodsFirst, we created a rat model of acute pressure overload cardiac hypertrophy by abdominal aortic banding. Protein expression time courses for β-catenin, glycogen synthase kinase-3β, and phosphoserine9-glycogen synthase kinase-3β were then examined. The rats were divided into four groups: normal rats with or without lithium administration and pressure-overloaded rats with or without lithium administration. Two days after surgery, Western blot analysis of β-catenin, echo-cardiographic evaluation, left ventricular (LV) weight, and LV atrial natriuretic peptide mRNA levels were evaluated.ResultsWe observed an increase in the level of glycogen synthase kinase-3β phosphorylation on Ser 9. A significant enhancement of LV heart weight (P < 0.05) and interventricular septum and posterior wall thickness (P < 0.05) with pressure-overloaded hypertrophy in animals treated with lithium were also observed. Atrial natriuretic peptide mRNA levels were significantly increased with pressure overload hypertrophy in animals treated with lithium.ConclusionsWe have shown in an animal model that inhibition of glycogen synthase kinase-3β by lithium has an additive effect on pressure overload cardiac hypertrophy.

Repair of Ebstein's anomaly in neonates and small infants: impact of right ventricular exclusion and its indications

OBJECTIVES In cases of severe Ebsteins anomaly, it is essential to determine whether biventricular repair (BVR) or single-ventricle palliation is feasible. Since 1999, in our institution, we have used the novel technique comprising tricuspid valve (TV) closure and right ventricular and right atrial (RV/RA) exclusion to reduce the deleterious effects of an enlarged RV in patients with severe Ebsteins anomaly. However, in cases with good RV function, primary BVR is performed. In the present study, we describe our surgical strategy in the treatment of severely symptomatic neonates with Ebsteins anomaly. METHODS From June 1999 to October 2011, 12 neonates with a severely symptomatic Ebsteins anomaly underwent surgical repair. The mean age at the first operation was 29 ± 25 (range, 5-92) days; and the mean body weight was 2.8 ± 0.5 (range, 2.0-4.1) kg. The associated anomalies included pulmonary atresia with an intact ventricular septum in 7, critical pulmonary stenosis in 1, ventricular septal defect in 3 and coarctation of the aorta in 1 patient. The mean cardio-thoracic ratio (CTR) was 80 ± 14% (range, 57-98%). Preoperatively, 9 patients had grade IV tricuspid regurgitation (TR), as detected by echocardiography, and 6 required ventilator support. RESULTS Five patients underwent primary BVR. Seven patients underwent staged palliation using a modified Blalock-Taussig shunt (BT shunt) with/without RV/RA exclusion. There was 1 case each of hospital death and late death. The median follow-up duration in the present study was 6.5 years. Among the 8 patients who underwent TV repair, postoperative TR was trivial or mild in 6 patients, moderate in 1 and absent in 1. After surgery, the mean CTR and serum B-type natriuretic peptide levels decreased to 59 ± 14% (range, 45-70%) and 46 ± 28 (range, 12-83) pg/dl, respectively. CONCLUSIONS Critically ill neonates with Ebsteins anomaly can be successfully treated using RV/RA exclusion combined with a modified BT shunt in cases where RV function is poor. However, in cases of good RV function, we recommend the use of primary BVR.

Atrioventricular Valve Repair for Patient With Heterotaxy Syndrome and a Functional Single Ventricle

Heterotaxy syndrome is a mortality risk factor for patients with complex heart disease. These patients often have common atrioventricular valve (CAVV) morphology and significant atrioventricular valve regurgitation - yet another mortality risk factor in congenital heart disease. Thus, patients with both heterotaxy syndrome and atrioventricular valve regurgitation are at highest risk of mortality. A large number of patients with heterotaxy syndrome have CAVV and a functional single ventricle. These patients are more difficult to operate than patients with biventricular morphology because in the former, the CAVV is often less adapted to systemic afterload than the mitral valve. Herein, we present the results of atrioventricular valve repair surgeries performed at the Okayama University Hospital on patients with heterotaxy syndrome, atrial isomerism, and a functional single ventricle. In addition, we review the current literature in this typically challenging patient population. In-depth understanding of reasonable management strategies and resolution of technical issues will help guide surgeons during this procedure.

Radial Incision for Ventricular Septal Defect with Membranous Septal Aneurysm

Surgical exposure and accurate closure of a ventricular septal defect with a membranous septal aneurysm beneath the septal tricuspid leaflet carries a risk of tricuspid valve dehiscence and conduction disturbances when the septal leaflet is detached along the tricuspid annulus. To avoid these problems, we use a radial incision to expose and close perimembranous ventricular septal defects. We reviewed recent cases to determine the risks and benefits of this technique. From January 2005 through September 2008, 30 patients underwent closure of a perimembranous ventricular septal defect through a right atrial approach at our institution. The operation included radial incision of the membranous septal aneurysm to improve visualization of the perimembranous ventricular septal defect in 9 patients. There was no perioperative or late death. The operative and postoperative courses were uneventful in all cases. A residual leak was detected in only one patient. No patient had more than mild postoperative tricuspid valve insufficiency, none underwent reoperation, and no new arrhythmia or conduction disturbance was detected during follow-up. The radial incision for closure of a ventricular septal defect with a membranous septal aneurysm provides satisfactory exposure of the defect through the right atriotomy, for safe and accurate closure.

Intracoronary Autologous Cardiac Progenitor Cell Transfer in Patients With Hypoplastic Left Heart Syndrome

Rationale: Hypoplastic left heart syndrome (HLHS) remains a lethal congenital cardiac defect. Recent studies have suggested that intracoronary administration of autologous cardiosphere-derived cells (CDCs) may improve ventricular function. Objective: The aim of this study was to test whether intracoronary delivery of CDCs is feasible and safe in patients with hypoplastic left heart syndrome. Methods and Results: Between January 5, 2011, and January 16, 2012, 14 patients (1.8±1.5 years) were prospectively assigned to receive intracoronary infusion of autologous CDCs 33.4±8.1 days after staged procedures (n=7), followed by 7 controls with standard palliation alone. The primary end point was to assess the safety, and the secondary end point included the preliminary efficacy to verify the right ventricular ejection fraction improvements between baseline and 3 months. Manufacturing and intracoronary delivery of CDCs were feasible, and no serious adverse events were reported within the 18-month follow-up. Patients treated with CDCs showed right ventricular ejection fraction improvement from baseline to 3-month follow-up (46.9%±4.6% to 52.1%±2.4%; P=0.008). Compared with controls at 18 months, cardiac MRI analysis of CDC-treated patients showed a higher right ventricular ejection fraction (31.5%±6.8% versus 40.4%±7.6%; P=0.049), improved somatic growth (P=0.0005), reduced heart failure status (P=0.003), and lower incidence of coil occlusion for collaterals (P=0.007). Conclusions: Intracoronary infusion of autologous CDCs seems to be feasible and safe in children with hypoplastic left heart syndrome after staged surgery. Large phase 2 trials are warranted to examine the potential effects of cardiac function improvements and the long-term benefits of clinical outcomes. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01273857.

Aortic Relocation for Transposition Complex with Aortic Arch Obstruction

We describe successful primary repair of 2 cases of transposition complex with aortic arch obstruction. A new aortic arch was reconstructed by direct anastomosis between the well-mobilized ascending aorta and the descending aorta. The neoaortic root with transferred coronary arteries was subsequently anastomosed to the undersurface of this new aortic arch. This technique deals with the significant size discrepancy between the 2 great arteries, and anomalous coronary artery patterns.

Pulmonary autograft patch aortoplasty for reconstruction of an interrupted aortic arch associated with an aortopulmonary window

We present here an infant with an aortopulmonary window associated with an interrupted aortic arch. Single-stage repair with a pulmonary autograft patch for augmentation of the interrupted aortic arch repair was performed. Transpulmonary patch closure was used to repair the aortopulmonary window. A computed tomography scan at the 1-month follow-up demonstrated a reconstructed aortic arch without obstruction, kinking, or any sign of bronchial or branch pulmonary artery compression.

Intracoronary Autologous Cardiac Progenitor Cell Transfer in Patients With Hypoplastic Left Heart SyndromeNovelty and Significance

Rationale: Hypoplastic left heart syndrome (HLHS) remains a lethal congenital cardiac defect. Recent studies have suggested that intracoronary administration of autologous cardiosphere-derived cells (CDCs) may improve ventricular function. Objective: The aim of this study was to test whether intracoronary delivery of CDCs is feasible and safe in patients with hypoplastic left heart syndrome. Methods and Results: Between January 5, 2011, and January 16, 2012, 14 patients (1.8±1.5 years) were prospectively assigned to receive intracoronary infusion of autologous CDCs 33.4±8.1 days after staged procedures (n=7), followed by 7 controls with standard palliation alone. The primary end point was to assess the safety, and the secondary end point included the preliminary efficacy to verify the right ventricular ejection fraction improvements between baseline and 3 months. Manufacturing and intracoronary delivery of CDCs were feasible, and no serious adverse events were reported within the 18-month follow-up. Patients treated with CDCs showed right ventricular ejection fraction improvement from baseline to 3-month follow-up (46.9%±4.6% to 52.1%±2.4%; P=0.008). Compared with controls at 18 months, cardiac MRI analysis of CDC-treated patients showed a higher right ventricular ejection fraction (31.5%±6.8% versus 40.4%±7.6%; P=0.049), improved somatic growth (P=0.0005), reduced heart failure status (P=0.003), and lower incidence of coil occlusion for collaterals (P=0.007). Conclusions: Intracoronary infusion of autologous CDCs seems to be feasible and safe in children with hypoplastic left heart syndrome after staged surgery. Large phase 2 trials are warranted to examine the potential effects of cardiac function improvements and the long-term benefits of clinical outcomes. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01273857.