Yosuke Kuroko

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.

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.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 cardiosphere-derived cells (CDCs) may be effective against congenital heart failure. Objective: To determine if 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 41 patients in a 1:1 ratio who had single ventricle physiology undergoing staged-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 cardiac function improvement at 3-month follow-up. Four months after palliation, controls had an alternative option to receive late CDC-infusion upon request (study B). Secondary outcomes included ventricular function, heart failure status, somatic growth, and health-related quality of life (QOL) after a 12-month observation. At 3 months, the absolute changes in ventricular function were significantly greater in the CDC-treated group than in controls (+6.4% [SD 5.5] vs. +1.3% [3.7]; P=0.003). In study B, a late CDC-infusion in 17 controls increased the ventricular function at 3 months compared with baseline (38.8% [SD 7.7] vs. 34.8% [7.4]; P<0.0001). At 1 year, overall CDC infusion was associated with improved ventricular function (41.4% [SD 6.6] vs. 35.0% [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 QOL, 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 QOL in patients, and reduce parenting stress for their families. Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT01829750.

Intracoronary Cardiac Progenitor Cells in Single Ventricle PhysiologyNovelty and Significance: 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.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 cardiosphere-derived cells (CDCs) may be effective against congenital heart failure. Objective: To determine if 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 41 patients in a 1:1 ratio who had single ventricle physiology undergoing staged-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 cardiac function improvement at 3-month follow-up. Four months after palliation, controls had an alternative option to receive late CDC-infusion upon request (study B). Secondary outcomes included ventricular function, heart failure status, somatic growth, and health-related quality of life (QOL) after a 12-month observation. At 3 months, the absolute changes in ventricular function were significantly greater in the CDC-treated group than in controls (+6.4% [SD 5.5] vs. +1.3% [3.7]; P=0.003). In study B, a late CDC-infusion in 17 controls increased the ventricular function at 3 months compared with baseline (38.8% [SD 7.7] vs. 34.8% [7.4]; P<0.0001). At 1 year, overall CDC infusion was associated with improved ventricular function (41.4% [SD 6.6] vs. 35.0% [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 QOL, 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 QOL in patients, and reduce parenting stress for their families. Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT01829750.

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.

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.

Advantages of temporary venoatrial shunt using centrifugal pump during bidirectional cavopulmonary shunt

Single-ventricle palliation without the use of cardiopulmonary bypass carries advantages that reduce systemic edema and inflammatory responses; however, simple clamping of the superior vena cava (SVC) without a temporary shunt leads to increase in cerebral venous pressure and subsequent decrease in cerebral blood flow during bidirectional cavopulmonary shunt (BCPS). We report our experience of BCPS, using a centrifugal pump–assisted temporary shunt. The criteria included an unrestrictive interatrial communication, the absence of atrioventricular valve regurgitation, and the existence of an antegrade pulmonary blood flow. From August 2000, 14 children with single-ventricle physiology met the criteria. The mean age was 1.0 ± 0.9 years, and the mean weight was 8.4 ± 2.6 kg. A temporary shunt was established between the SVC and the right atrium with right-angle cannulae, which were connected to a centrifugal pump to accelerate the blood flow from the SVC to the right atrium. All patients tolerated the procedure. Mean central venous pressure was 17 ± 4 mm Hg, and transcutaneous oxygen saturation was maintained at 77 ± 8% during anastomosis. No patients required blood transfusion. There were no postoperative neurological complications. The centrifugal pump–assisted temporary shunt offered safer and more effective circulatory support than other shunt systems, with excellent venous drainage in pediatric patients undergoing BCPS.

Contribution of catechol O-methyltransferase to the removal of accumulated interstitial catecholamines evoked by myocardial ischemia

Catechol O-methyltransferase (COMT) plays an important role for clearance of high catecholamine levels. Although myocardial ischemia evokes similar excessive catecholamine accumulation, it is uncertain whether COMT activity is involved in the removal of accumulated catecholamines evoked by myocardial ischemia. We examined how COMT activity affects myocardial catecholamine levels during myocardial ischemia and reperfusion. We implanted a dialysis probe into the left ventricular myocardial free wall and measured dialysate catecholamines levels in anesthetized rabbits. Dialysate catecholamine levels served as an index of myocardial interstitial catecholamine levels. We introduced myocardial ischemia by 60 min occlusion of the main coronary artery. The ischemia-induced dialysate catecholamines levels were compared with and without the pretreatment with entacapone (COMT inhibitor, 10 mg/kg, i.p.). Acute myocardial ischemia progressively increased dialysate catecholamine levels. Acute myocardial ischemia increased dialysate norepinephrine (NE) levels (20,453+/-7186 pg/ml), epinephrine (EPI) levels (1724+/-706 pg/ml), and dopamine (DA) levels (1807+/-800 pg/ml) at the last 15 min of coronary occlusion. Inhibition of COMT activity by entacapone augmented the ischemia-induced NE levels (54,306+/-6618 pg/ml), EPI levels (2681+/-567 pg/ml), and DA (3551+/-710 pg/ml) levels at the last 15 min of coronary occlusion. Myocardial ischemia evoked NE, EPI, and DA accumulation in the myocardial interstitial space. The inhibition of COMT activity augmented these increments in NE, EPI, and DA. These data suggest that cardiac COMT activity influences on the removal of accumulated catecholamine during myocardial ischemia.

Effects of intravenous cariporide on release of norepinephrine and myoglobin during myocardial ischemia/reperfusion in rabbits

AIMS To examine the effects of cariporide, a Na(+)/H(+) exchanger-1 inhibitor, on cardiac norepinephrine (NE) and myoglobin release during myocardial ischemia/reperfusion by applying a microdialysis technique to the rabbit heart. MAIN METHODS In anesthetized rabbits, two dialysis probes were implanted into the left ventricular myocardium and were perfused with Ringers solution. Cariporide (0.3mg/kg) was injected intravenously, followed by occlusion of the left circumflex coronary artery. During 30-min coronary occlusion followed by 30-min reperfusion, four consecutive 15-min dialysate samples (two during ischemia and two during reperfusion) were collected in vehicle and cariporide-treated groups. Dialysate myoglobin and NE concentrations were measured by immunochemistry and high-performance liquid chromatography, respectively. KEY FINDINGS Dialysate myoglobin and NE concentrations increased significantly during myocardial ischemia/reperfusion in both vehicle and cariporide-treated groups (P<0.01 vs. baseline). In cariporide-treated group, dialysate myoglobin concentrations were significantly lower than those in vehicle group throughout ischemia/reperfusion (P<0.01 at 0-15 min of ischemia, P<0.05 at 15-30 min of ischemia, P<0.01 at 0-15 min of reperfusion, and P<0.01 at 15-30 min of reperfusion). However, dialysate NE concentrations in cariporide-treated group were lower than those in vehicle group only during ischemia (P<0.01 at 0-15 min of ischemia, and P<0.05 at 15-30 min of ischemia). SIGNIFICANCE When administered before ischemia, cariporide reduces myoglobin release during ischemia/reperfusion and decreases NE release during ischemia.

Intracoronary Cardiac Progenitor Cells in Single Ventricle Physiology: The PERSEUS 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.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 cardiosphere-derived cells (CDCs) may be effective against congenital heart failure. Objective: To determine if 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 41 patients in a 1:1 ratio who had single ventricle physiology undergoing staged-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 cardiac function improvement at 3-month follow-up. Four months after palliation, controls had an alternative option to receive late CDC-infusion upon request (study B). Secondary outcomes included ventricular function, heart failure status, somatic growth, and health-related quality of life (QOL) after a 12-month observation. At 3 months, the absolute changes in ventricular function were significantly greater in the CDC-treated group than in controls (+6.4% [SD 5.5] vs. +1.3% [3.7]; P=0.003). In study B, a late CDC-infusion in 17 controls increased the ventricular function at 3 months compared with baseline (38.8% [SD 7.7] vs. 34.8% [7.4]; P<0.0001). At 1 year, overall CDC infusion was associated with improved ventricular function (41.4% [SD 6.6] vs. 35.0% [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 QOL, 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 QOL in patients, and reduce parenting stress for their families. Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT01829750.

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.