Intracoronary Cardiac Progenitor Cells in Single Ventricle Physiology: The PERSEUS (Cardiac Progenitor Cell Infusion to Treat Univentricular Heart Disease) Randomized Phase 2 Trial.

RATIONALE: Patients with single ventricle physiology are at high risk of mortality resulting from ventricular dysfunction. The preliminary results of the phase 1 trial showed that cardiosphere-derived cells (CDCs) may be effective against congenital heart failure. OBJECTIVE: To determine whether intracoronary delivery of autologous CDCs improves cardiac function in patients with single ventricle physiology. METHODS AND RESULTS: We conducted a phase 2 randomized controlled study to assign in a 1:1 ratio 41 patients who had single ventricle physiology undergoing stage 2 or 3 palliation to receive intracoronary infusion of CDCs 4 to 9 weeks after surgery or staged reconstruction alone (study A). The primary outcome measure was to assess improvement in cardiac function at 3-month follow-up. Four months after palliation, controls had an alternative option to receive late CDC infusion on request (study B). Secondary outcomes included ventricular function, heart failure status, somatic growth, and health-related quality of life after a 12-month observation. At 3 months, the absolute changes in ventricular function were significantly greater in the CDC-treated group than in the controls (+6.4% [SD, 5.5] versus +1.3% [SD, 3.7]; P=0.003). In study B, a late CDC infusion in 17 controls increased the ventricular function at 3 months compared with that at baseline (38.8% [SD, 7.7] versus 34.8% [SD, 7.4]; P<0.0001). At 1 year, overall CDC infusion was associated with improved ventricular function (41.4% [SD, 6.6] versus 35.0% [SD, 8.2]; P<0.0001) and volumes (P<0.001), somatic growth (P<0.0001) with increased trophic factors production, such as insulin-like growth factor-1 and hepatocyte growth factor, and quality of life, along with a reduced heart failure status (P<0.0001) and cardiac fibrosis (P=0.014) relative to baseline. CONCLUSIONS: Intracoronary infusion of CDCs after staged palliation favorably affected cardiac function by reverse remodeling in patients with single ventricle physiology. This impact may improve heart failure status, somatic growth, and quality of life in patients and reduce parenting stress for their families. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01829750.

A staged decompression of right ventricle allows growth of right ventricle and subsequent biventricular repair in patients with pulmonary atresia and intact ventricular septum.

OBJECTIVES: To achieve the growth of right-sided heart structures, our choice of the first palliation for patients with pulmonary atresia and intact ventricular septum (PA-IVS) includes a modified Blalock-Taussig shunt (BTS) with pulmonary valvotomy. We sought to analyse the impact of the first palliation on the growth of right-sided heart structures and factors associated with a choice of definitive surgical procedure. METHODS: Fifty patients with PA-IVS who underwent a staged surgical approach from 1991 to 2012 were retrospectively reviewed. RESULTS: Right ventricular (RV)-coronary artery fistulas were seen in 42% of patients at the time of birth. All 50 patients had a modified BTS with pulmonary valvotomy. Six patients died after the first palliation or inter-stage. Thirty patients achieved a biventricular repair (BVR group), 6 patients had a 1 + 1/2 ventricular repair (1 + 1/2V group) and 5 patients had a Fontan completion (Fontan group). After modified BTS with pulmonary valvotomy, tricuspid valve z-score did not increase in any of the group (BVR: pre -2.79 vs post -2.24, 1 + 1/2V: pre -5.25 vs post -6.69, Fontan: pre -6.82 vs post -7.94). Normalized RV end-diastolic volume increased only in BVR group after modified BTS with pulmonary valvotomy (BVR: pre 32% vs post 64%, 1 + 1/2V: pre 43% vs post 42%, Fontan: pre 29% vs post 32%). Major RV-coronary artery fistula was a strong factor with proceeding single-ventricle palliation [BVR: 4/30 (13%) patients, 1 + 1/2V: 1/6 (17%) and Fontan: 4/5 (80%)]. CONCLUSIONS: Tricuspid valve growth was not obtained by modified BTS with pulmonary valvotomy; therefore, tricuspid valve size at birth appeared to be a predictor for achieving BVR. Proportionate RV growth was seen only in patients who achieved BVR. However, RV growth was not seen in patients having 1 + 1/2 ventricular repair. Major RV-coronary artery fistula was a strong predictor for proceeding single-ventricle palliation.

A prospective randomized trial comparing the clinical effectiveness and biocompatibility of heparin-coated circuits and PMEA-coated circuits in pediatric cardiopulmonary bypass.

OBJECT: We compared the clinical effectiveness and biocompatibility of poly-2-methoxyethyl acrylate (PMEA)-coated and heparin-coated cardiopulmonary bypass (CPB) circuits in a prospective pediatric trial. METHODS: Infants randomly received heparin-coated (n=7) or PMEA-coated (n=7) circuits in elective pediatric cardiac surgery with CPB for ventricular septum defects. Clinical and hematologic variables, respiratory indices and hemodynamic changes were analyzed perioperatively. RESULTS: Demographic and clinical variables were similar in both groups. Leukocyte counts were significantly lower 5 minutes after CPB in the PMEA group than the heparin group. Hemodynamic data showed that PMEA caused hypotension within 5 minutes of CPB. The respiratory index was significantly higher immediately after CPB and 1 hour after transfer to the intensive care unit (ICU) in the PMEA group, as were levels of C-reactive protein 24 hours after transfer to the ICU. CONCLUSION: Our study shows that PMEA-coated circuits, unlike heparin-coated circuits, cause transient leukopenia during pediatric CPB and, perhaps, systemic inflammatory respiratory syndrome after pediatric CPB.

Novel Model of Pulmonary Artery Banding Leading to Right Heart Failure in Rats.

BACKGROUND: Congenital heart diseases often involve chronic pressure overload of the right ventricle (RV) which is a major cause of RV dysfunction. Pulmonary artery (PA) banding has been used to produce animal models of RV dysfunction. We have devised a new and easier method of constricting the PA and compared it directly with the partial ligation method. METHODS: Eight-week-old male Sprague-Dawley rats (240-260 g) were divided into three groups: sham operation, partial pulmonary artery ligation (PAL) procedure, and pulmonary artery half-closed clip (PAC) procedure. RV function and remodeling were determined by echocardiography and histomorphometry. RESULTS: Surgical mortality was significantly lower in the PAC group while echocardiography revealed significantly more signs of RV dysfunction. At the 8th week after surgery RV fibrosis rate was significantly higher in the PAC group. CONCLUSIONS: This procedure of pulmonary artery banding in rats is easier and more efficient than partial ligation.

Surgical outcome of hypoplastic left heart syndrome with intact atrial septum.

BACKGROUND: The surgical outcomes of hypoplastic left heart syndrome with intact atrial septum remains very poor in spite of the introduction of prenatal diagnosis before the Norwood operation. The hybrid operation consisting of bilateral pulmonary artery banding and balloon atrioseptectomy is one of the treatment strategies to potentially improve this patient population, however, the long-term outcomes are unknown. METHODS: Six consecutive patients with hypoplastic left heart syndrome with intact atrial septum, who underwent the hybrid operation between October 2006 and July 2014, were retrospectively reviewed. Hypoplastic left heart syndrome with highly restrictive atrial communication was excluded. RESULTS: Three patients died after the hybrid operation, due to sepsis, cerebral bleeding, and heart failure. Three patients underwent the modified Norwood operation. One of these died due to severe hypoxia while awaiting the bidirectional Glenn operation. The others underwent a bidirectional Glenn operation and subsequent Fontan completion but died due to lung dysfunction and sudden hemoptysis. CONCLUSIONS: The hybrid operation for hypoplastic left heart syndrome with intact atrial septum may have improved the neonatal outcome and Fontan completion rate in this extremely high-risk group of patients, but the long-term outcome remains dismal. Considering the late mortality related to pulmonary complications, aggressive fetal intervention to create a nonrestrictive atrial septal communication to promote normal development of the pulmonary vessels may be the last resort to improve the long-term outcome.

Left Ventricular Myxoma Occluding the Suprarenal Abdominal Aorta in an Infant.

Myxoma is the most common primary cardiac tumor in adults; however, it is extremely rare in infants. Acute occlusion of the abdominal aorta by a cardiac myxoma is also rare. We report the case of an infant with acute occlusion of the suprarenal abdominal aorta by a left ventricular myxoma. The patient underwent successful catheter embolectomy of the abdominal aorta and surgical resection of the cardiac myxoma. This is a very rare case report of the combination of infantile left ventricular myxoma and acute occlusion of the abdominal aorta.

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.

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

OBJECTIVES: In cases of severe Ebstein's 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 Ebstein's 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 Ebstein's anomaly. METHODS: From June 1999 to October 2011, 12 neonates with a severely symptomatic Ebstein's 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 Ebstein's 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.

The effect of pulmonary root translocation on the left ventricular outflow tract.

We report the effect of pulmonary root translocation on the left ventricular outflow tract. A double switch operation with pulmonary root translocation was performed in a 6-year-old boy whose diagnosis was dextrocardia, congenitally corrected transposition of the great arteries, ventricular septal defect, and pulmonary stenosis. Postoperative magnetic resonance imaging showed more natural left ventricular outflow than preoperatively (19 mm vs 22 mm in length between the top of the interventricular septum and the aortic valve). This technique does not require coronary transfer and enables preservation of the aortic root structure. The long-term results, including left ventricular outflow tract morphology, should be evaluated.

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.

Double-barrel Damus-Kaye-Stansel operation is better than end-to-side Damus-Kaye-Stansel operation for preserving the pulmonary valve function: the importance of preserving the shape of the pulmonary sinus.

OBJECTIVE: The Damus-Kaye-Stansel operation sometimes results in deteriorating semilunar valve insufficiency. We verified the semilunar valve function after the Damus-Kaye-Stansel operation and compared the end-to-side Damus-Kaye-Stansel with the double-barrel Damus-Kaye-Stansel. METHODS: Forty-seven patients who underwent the Damus-Kaye-Stansel operation between June 1993 and August 2008 were retrospectively reviewed. Any patient who underwent a Norwood-type operation was excluded. The median age at operation was 19 months (range, 0-276 months). Forty-five patients were Fontan candidates. Thirty-nine patients underwent pulmonary artery banding before the Damus-Kaye-Stansel operation. Twenty-two patients had undergone an arch repair previously. The semilunar valve function was evaluated by echocardiography. RESULTS: Thirteen patients underwent the end-to-side Damus-Kaye-Stansel operation, and 34 patients underwent the double-barrel Damus-Kaye-Stansel operation. The mean follow-up period was 71 ± 50 months (range, 1-188 months). Although there were 4 deaths, no death was related to the Damus-Kaye-Stansel procedure. Two of the patients with early death could not undergo a postoperative evaluation of the semilunar valves. The semilunar valve regurgitation mildly deteriorated in 7 patients (pulmonary regurgitation in 5 patients and aortic regurgitation in 2 patients). Pulmonary regurgitation deteriorated from none to mild in 1 patient, none to trivial in 2 patients, and trivial to mild in 2 patients. Both deteriorations in aortic regurgitation ranged from none to trivial. Semilunar valve regurgitation did not affect patients' circulatory condition. The end-to-side Damus-Kaye-Stansel operation more frequently caused a deterioration in pulmonary regurgitation than the double-barrel Damus-Kaye-Stansel operation (4/11 vs 1/34, P = .001). No surgical intervention for a systemic ventricular outflow obstruction was observed in the follow-up period. CONCLUSIONS: The double-barrel Damus-Kaye-Stansel operation was found to be superior to the end-to-side Damus-Kaye-Stansel operation for the prevention of postoperative pulmonary regurgitation.

Extracorporeal membrane oxygenation following Norwood stage 1 procedures at a single institution.

Extracorporeal membrane oxygenation (ECMO) is an important circulatory assist for children with refractory cardiopulmonary dysfunction, but its role and indications after a stage 1 Norwood procedure are controversial. We assessed outcomes and risk factors in patients who underwent a Norwood palliation and ECMO at our institution. We retrospectively reviewed all patients who underwent a Norwood procedure and were supported with ECMO between January 1998 and January 2010. Of the 91 children who underwent a Norwood procedure during the study period, there were 15 postoperative runs of ECMO in 12 patients. The diagnoses of the patients included five with hypoplastic left heart syndrome, five with a hypoplastic left heart syndrome variant, and two with critical aortic stenosis. A total of four patients underwent bilateral pulmonary artery banding, and two patients underwent aortic valvuloplasty before the stage 1 Norwood procedure. The mean age of the patients was 28±30 days, and mean body weight was 2.6±0.5kg at the induction of ECMO. The indications for ECMO were low cardiac output in six children, circulatory collapse needing cardiopulmonary resuscitation in six children, and hypoxemia in three children. Five of the 12 patients were successfully weaned from ECMO. The significant risk factors for the inability to be weaned from ECMO were a history of circulatory collapse requiring cardiopulmonary resuscitation, and the induction of ECMO in the intensive care unit. Induction of ECMO may be considered earlier when hemodynamics are unstable in impaired patients following a stage 1 Norwood procedure to avoid circulatory collapse.

Combination of continuous irrigation and vacuum-assisted closure is effective for mediastinitis after cardiac surgery in small children.

There is still no consensus on the optimal management to treat pediatric mediastinitis. We assessed the efficacy of continuous irrigation and vacuum-assisted closure (VAC) for mediastinitis in children. This study retrospectively reviewed 20 patients aged <5 years with mediastinitis from December 2002 to December 2009. The median age at the onset was 12 months (0.6-60 months), and the median body weight was 6.9 kg (3.1-15.3 kg). Continuous irrigation was applied for extensive mediastinitis or unstable hemodynamic cases and VAC for localized or ineffective cases after continuous irrigation. A 2-4-week course of intravenous antibiotics was administered after sternal closure. Continuous irrigation was initially applied in 19 patients and VAC in one patient. VAC was employed in six patients because of recurrent or prolonged mediastinitis after continuous irrigation. All patients underwent direct sternal closure without any flap. The median duration of the hospital stay was 49.5 days (15-158 days). Although two patients died of low cardiac output, 18 children survived and had no recurrence after the discharge during a median follow-up of 14 months (1-81 months). The combination of continuous irrigation and VAC is, therefore, considered to be a safe and effective option to minimize the morbidity and mortality in pediatric mediastinitis.

Growth of the lateral tunnel in patients who underwent a total cavopulmonary connection at less than 5 years of age.

OBJECTIVE: A lateral tunnel-total cavopulmonary connection (LT-TCPC) using a right atrial (RA) free wall is the first choice of treatment for patients with a small body weight in this institute. Whether the growth of the LT is appropriate or not according to the growth of the body remains controversial. In addition, the optimal initial diameter of an LT is unknown. The purpose of this study was to verify the growth of the LT. METHODS: Ninety-one patients of a total of 267 TCPC cases underwent an LT-TCPC at less than 5 years of age in this institute between March 1991 and June 2008. The data on 47 of the 91 patients, which were available to investigate the LT growth, were retrospectively reviewed. The mean age at LT-TCPC was 37+/-11 months (16-57 months). The mean body weight at TCPC was 12.4+/-2.4 kg (7.6-20.0 kg). The initial LT diameter was determined with Hegar's sizer of the estimated half-pulmonary arterial (PA) diameter, which is a diameter that results in half of the dimension of the normal pulmonary valve. The measured maximum LT diameter (mm) divided by the estimated half-PA diameter (mm) was considered as the LT index. The size of the LT was evaluated using either echocardiography or angiography. RESULTS: The mean follow-up period was 7.4+/-3.5 years (1.6-13.5 years). The LT index was initially 2.0+/-0.7 (1.3-4.5), 2.0+/-0.4 (1.3-3.2) at 1 year after operation, 2.1+/-0.5 (1.5-3.2) at 5 years after operation, 1.9+/-0.4 (1.5-2.8) at 10 years after operation and 2.1+/-0.5 (1.6-2.5) at 13 years after operation, respectively. CONCLUSIONS: LT growth suitable for the body growth can be expected. Although there was some variation in the initial LT diameter, the LT index tended to converge at 2.0 with growth.

The impact of the length between the top of the interventricular septum and the aortic valve on the indications for a biventricular repair in patients with a transposition of the great arteries or a double outlet right ventricle.

The purpose of this study was to establish a useful cut-off level for performing an original Rastelli-type operation in patients with transposition of the great arteries (TGA)/ventricular septal defect (VSD) or double outlet right ventricle (DORV). A total of 43 patients with TGA/VSD or DORV who underwent an original Rastelli-type operation in this institute between March 1993 and January 2009 were reviewed retrospectively. These patients were divided into two groups using the length between the top of the interventricular septum and the aortic valve (IVS-AV length); Group A; IVS-AV length <80% of normal left ventricular end-diastolic diameter (LVDd). Group B; IVS-AV length > or =80% of normal LVDd. Group A had a significantly better survival than Group B (100% vs. 56%, P=0.001). The cardiac event-free survival were 89.1% at 7.2 years in Group A and 26.3% at 8.4 years in Group B (P<0.0001). The Group B had a higher incidence of left ventricular outflow tract obstruction (LVOTO; 3% vs. 33%, P=0.02). The IVS-AV length was found to be a significant risk factor for mortality and LVOTO. The IVS-AV length should, therefore, be taken into consideration when selecting the optimal surgical procedures for these patients.

The rewarming index formula for pediatric cardiopulmonary perfusion.

Careful rewarming of perfusion blood following cardiopulmonary bypass surgery is critical to a successful outcome, but the optimal rewarming strategy is not clear. The purpose of this study was to derive a formula for a rewarming index (defined as [rewarming time x perfusion flow]/[body weight x body surface area]) that would enable the calculation of the ideal rewarming conditions for pediatric cardiopulmonary perfusion. We retrospectively investigated 220 pediatric cardiopulmonary bypass operations conducted from July 2005 to June 2008 in Okayama University Hospital, Japan. We determined the formula as Phi = (T x Q)/(R x S) = |0.9127P - 0.0152|, where Phi = rewarming index, T = rewarming time (min), Q = perfusion volume (L), R = body weight (kg), S = body surface area (m(2)), and P = temperature gap (right angle). The formula will help those who perform pediatric cardiopulmonary bypass surgery to establish ideal perfusion flow conditions and to control physiological temperature during rewarming.

The benefits of high-flow management in children with pulmonary atresia.

The high-flow management of cardiopulmonary bypass (CPB; >or=2.4 L/min/m(2)) is a standard strategy used at this institute for children with pulmonary atresia (PA) due to a fear that the blood flow may be diverted by the major/minor aortopulmonary-collateral-arteries and hypervascularization due to long-term hypoxia. The purpose of this study was to describe the validity of high-flow management in children with PA. The CPB records of 23 children with PA who underwent a definitive biventricular repair between Feb 2006 and Nov 2008 were retrospectively reviewed. The mean age at the operation was 33 +/- 22 months. The blood-pressure during bypass was controlled with the same protocol. The mean cooling-temperature was 28.4 +/- 3.7 degrees C. The mean minimum hematocrit was 25.0 +/- 3.4%. The mean maximum bypass flow index at the initiation, the mean maximum flow index during aortic cross-clamping, the mean minimum flow index during aortic cross-clamping, and the mean maximum flow index after rewarming were 3.1 +/- 0.5, 3.1 +/- 0.5, 2.6 +/- 0.4, and 3.2 +/- 0.4 L/min/m(2), respectively. The higher bypass flow indexes significantly correlated with the lower serum lactate levels. The lowest oxygen delivery during CPB had significant influences on the urine output during bypass (R = 0.547, P = 0.007), the serum lactate levels at the end of CPB (R = -0.442, P = 0.035), and the postoperative thoracic effusion (R = -0.459, P = 0.028). A bypass flow index of 2.4 L/min/m(2) may not be sufficient and the maximum requirement of bypass flow index may be 3.2 L/min/m(2) or more in this patient population.