Intravenous infusion of cardiac progenitor cells in animal models of single ventricular physiology.

OBJECTIVES: The goal of this study was to identify the practical applications of intravenous cell therapy for single-ventricle physiology (SVP) by establishing experimental SVP models. METHODS: An SVP with a three-stage palliation was constructed in an acute swine model without cardiopulmonary bypass. A modified Blalock-Taussig (MBT) shunt was created using an aortopulmonary shunt with the superior and inferior venae cavae (SVC and IVC, respectively) connected to the left atrium (n = 10). A bidirectional cavopulmonary shunt (BCPS) was constructed using a graft between the IVC and the left atrium with an SVC cavopulmonary connection (n = 10). The SVC and the IVC were connected to the pulmonary artery to establish a total cavopulmonary connection (TCPC, n = 10). The survival times of half of the animal models were studied. The other half and the biventricular sham control (n = 5) were injected intravenously with cardiosphere-derived cells (CDCs), and the cardiac retention of CDCs was assessed after 2 h. RESULTS: All SVP models died within 20 h. Perioperative mortality was higher in the BCPS group because of lower oxygen saturation (P < 0.001). Cardiac retention of intravenously delivered CDCs, as detected by magnetic resonance imaging and histologic analysis, was significantly higher in the modified Blalock-Taussig and BCPS groups than in the TCPC group (P < 0.01). CONCLUSIONS: Without the total right heart exclusion, stage-specific SVP models can be functionally constructed in pigs with stable outcomes. Intravenous CDC injections may be applicable in patients with SVP before TCPC completion, given that the initial lung trafficking is efficiently bypassed and sufficient systemic blood flow is supplied from the single ventricle.

Diamond-like carbon coating to inner surface of polyurethane tube reduces Staphylococcus aureus bacterial adhesion and biofilm formation.

Staphylococcus aureus is one of the main causative bacteria for polyurethane catheter and artificial graft infection. Recently, we developed a unique technique for coating diamond-like carbon (DLC) inside the luminal resin structure of polyurethane tubes. This study aimed to elucidate the infection-preventing effects of diamond-like carbon (DLC) coating on a polyurethane surface against S. aureus. We applied DLC to polyurethane tubes and rolled polyurethane sheets with our newly developed DLC coating technique for resin tubes. The DLC-coated and uncoated polyurethane surfaces were tested in smoothness, hydrophilicity, zeta-potential, and anti-bacterial properties against S. aureus (biofilm formation and bacterial attachment) by contact with bacterial fluids under static and flow conditions. The DLC-coated polyurethane surface was significantly smoother, more hydrophilic, and had a more negative zeta-potential than did the uncoated polyurethane surface. Upon exposure to bacterial fluid under both static and flow conditions, DLC-coated polyurethane exhibited significantly less biofilm formation than uncoated polyurethane, based on absorbance measurements. In addition, the adherence of S. aureus was significantly lower for DLC-coated polyurethane than for uncoated polyurethane under both conditions, based on scanning electron microscopy. These results show that applying DLC coating to the luminal resin of polyurethane tubes may impart antimicrobial effects against S. aureus to implantable medical polyurethane devices, such as vascular grafts and central venous catheters.

Comprehensive hemocompatibility analysis on the application of diamond-like carbon to ePTFE artificial vascular prosthesis.

The aim of this study was to obtain comprehensive data regarding the hemocompatibility of diamond-like carbon (DLC)-coated expanded polytetrafluoroethylene (ePTFE). DLC increased the hydrophilicity and smoothened the surface and fibrillar structure, respectively, of the ePTFE. DLC-coated ePTFE had more albumin and fibrinogen adsorption and less platelet adhesion than uncoated ePTFE. There were scarce red cell attachments in in vitro human and in vivo animal (rat and swine) whole blood contact tests in both DLC-coated and uncoated ePTFE. DLC-coated ePTFE had a similar but marginally thicker band movement than uncoated-ePTFE with SDS-PAGE after human whole blood contact test. In addition, survival studies of aortic graft replacement in rats (1.5 mm graft) and arteriovenous shunt in goats (4 mm graft) were performed to compare the patency and clot formation between DLC-coated and uncoated ePTFE grafts. Comparable patency was observed in both animal models. However, clots were observed in the luminal surface of the patent 1.5 mm DLC-coated ePTFE grafts, but not in that of uncoated ePTFE grafts. In conclusions, hemocompatibility of DLC-coated ePTFE was high and comparable to that of uncoated ePTFE. However, it failed to improve the hemocompatibility of 1.5 mm ePTFE graft probably because increased fibrinogen adsorption canceled the other beneficial effects of DLC.

Protective effects of an anti-4-HNE monoclonal antibody against liver injury and lethality of endotoxemia in mice.

4-hydroxy-2-nonenal (4-HNE) is a lipid peroxidation product that is known to be elevated during oxidative stress. During systemic inflammation and endotoxemia, plasma levels of 4-HNE are elevated in response to lipopolysaccharide (LPS) stimulation. 4-HNE is a highly reactive molecule due to its generation of both Schiff bases and Michael adducts with proteins, which may result in modulation of inflammatory signaling pathways. In this study, we report the production of a 4-HNE adduct-specific monoclonal antibody (mAb) and the effectiveness of the intravenous injection of this mAb (1 mg/kg) in ameliorating LPS (10 mg/kg, i.v.)-induced endotoxemia and liver injury in mice. Endotoxic lethality in control mAb-treated group was suppressed by the administration of anti-4-HNE mAb (75 vs. 27%). After LPS injection, we observed a significant increase in the plasma levels of AST, ALT, IL-6, TNF-α and MCP-1, and elevated expressions of IL-6, IL-10 and TNF-α in the liver. All these elevations were inhibited by anti-4-HNE mAb treatment. As to the underlining mechanism, anti-4-HNE mAb inhibited the elevation of plasma high mobility group box-1 (HMGB1) levels, the translocation and release of HMGB1 in the liver and the formation of 4-HNE adducts themselves, suggesting a functional role of extracellular 4-HNE adducts in hypercytokinemia and liver injury associated with HMGB1 mobilization. In summary, this study reveals a novel therapeutic application of anti-4-HNE mAb for endotoxemia.

[A new approach to combat the sepsis including COVID-19 by accelerating detoxification of hemolysis-related DAMPs].

Sepsis is one of the leading cause of death worldwide. Recently, several studies suggested that free-hemoglobin and heme derived from hemolysis are important factors which may be associated with severity of septic patients including COVID-19. In other words, hemolysis-derived products enhance the inflammatory responses as damage-associated molecular patterns (DAMPs) in both intravascular and extravascular space. In addition, hemoglobin has vasoconstrictive activity by depleting nitric oxide, whereas heme or Fe2+ produce reactive oxygen species (ROS) through Fenton reaction leading to tissue injury. At present, we have no therapeutic options against sepsis-related hemolysis in clinical settings, however, there might be two therapeutic strategies in this regard. One is supplemental therapy of depleted scavenging proteins such as haptoglobin and hemopexin, the other is activation of the internal scavenging system including macrophage-CD163 pathway. These novel targets against sepsis are also critical for the next pandemic. In this review, we summarize the current issues regarding sepsis-related hemolysis including COVID-19, as well as for future perspectives.

Treatment of Marmoset Intracerebral Hemorrhage with Humanized Anti-HMGB1 mAb.

Intracerebral hemorrhage (ICH) is recognized as a severe clinical problem lacking effective treatment. High mobility group box-1 (HMGB1) exhibits inflammatory cytokine-like activity once released into the extracellular space from the nuclei. We previously demonstrated that intravenous injection of rat anti-HMGB1 monoclonal antibody (mAb) remarkably ameliorated brain injury in a rat ICH model. Therefore, we developed a humanized anti-HMGB1 mAb (OKY001) for clinical use. The present study examined whether and how the humanized anti-HMGB1 mAb ameliorates ICH injury in common marmosets. The results show that administration of humanized anti-HMGB1 mAb inhibited HMGB1 release from the brain into plasma, in association with a decrease of 4-hydroxynonenal (4-HNE) accumulation and a decrease in cerebral iron deposition. In addition, humanized anti-HMGB1 mAb treatment resulted in a reduction in brain injury volume at 12 d after ICH induction. Our in vitro experiment showed that recombinant HMGB1 inhibited hemoglobin uptake by macrophages through CD163 in the presence of haptoglobin, suggesting that the release of excess HMGB1 from the brain may induce a delay in hemoglobin scavenging, thereby allowing the toxic effects of hemoglobin, heme, and Fe2+ to persist. Finally, humanized anti-HMGB1 mAb reduced body weight loss and improved behavioral performance after ICH. Taken together, these results suggest that intravenous injection of humanized anti-HMGB1 mAb has potential as a novel therapeutic strategy for ICH.

Initial evaluation of a novel electrocardiography sensor-embedded fabric wear during a full marathon.

Sudden cardiac accident (SCA) during a marathon is a concern due to the popularity of the sport. Preventive strategies, such as cardiac screening and deployment of automated external defibrillators have controversial cost-effectiveness. We investigated the feasibility of use of a new electrocardiography (ECG) sensor-embedded fabric wear (SFW) during a marathon as a novel preventive strategy against SCA. Twenty healthy volunteers participated in a full marathon race. They were equipped with a SFW hitoe® with a transmitter connected via Bluetooth to a standard smartphone for continuous ECG recording. All data were stored in a smartphone and used to analyze the data acquisition rate. The adequate data acquisition rate was > 90% in 13, 30-90% in 3, and < 10% in 4 runners. All of 4 runners with poorly recorded data were female. Inadequate data acquisition was significantly associated with the early phase of the race compared with the mid phase (P = 0.007). Except for 3 runners with poor heart rate data, automated software calculation was significantly associated with manual analysis for both the mean (P < 0.001) and maximum (P = 0.014) heart rate. We tested the feasibility of continuously recording cardiac data during a marathon using a new ECG sensor-embedded wearable device. Although data from 65% of runners were adequately recorded, female runners and the early phase of the race tended to have poor data acquisition. Further improvements in device ergonomics and software are necessary to improve ability to detect abnormal ECGs that may precede SCA.

Exercise-Induced Ischemic ST-Segment Elevation in Anomalous Origin of the Right Coronary Artery From the Left Sinus of Valsalva With an Intramural Course and Blocked Coronary Bypass.

Sudden cardiac events in young athletes are a major concern in the field of sports cardiology. Although coronary artery anomalies remain a major cause of cardiac events in young athletes, only a few cases have been diagnosed prior to critical events. Here, we present the case of a previously asymptomatic young male runner who experienced sudden cardiac arrest at the end of a marathon. The patient immediately received cardiopulmonary resuscitation from a bystander and was transported to an emergency hospital. As his electrocardiogram showed ventricular fibrillation, he was treated with electric shock, and his rhythm was successfully converted to a normal sinus rhythm. Following successful resuscitation, the patient was diagnosed with an anomalous origin of the right coronary artery from the left sinus of Valsalva with an intramural course. The patient underwent coronary artery bypass using the right internal thoracic artery. Fifteen years later, the coronary bypass was found to be blocked, but the patient was asymptomatic. However, an exercise electrocardiogram revealed ST-segment elevation in the inferior leads. The patient then underwent an unroofing procedure. He has remained asymptomatic without complications for two years after the second surgery.

Intraluminal diamond-like carbon coating with anti-adhesion and anti-biofilm effects for uropathogens: A novel technology applicable to urinary catheters.

OBJECTIVES: To examine anti-adhesion and anti-biofilm effects of a diamond-like carbon coating deposited via a novel technique on the inner surface of a thin silicon tube. METHODS: Diamond-like carbon coatings were deposited into the lumen of a silicon tube with inner diameters of 2 mm. The surface of the diamond-like carbon was evaluated using physicochemical methods. We used three clinical isolates including green fluorescent protein-expressing Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus. We employed a continuous flow system for evaluation of both bacterial adhesion and biofilm formation. Bacterial adhesion assays consisted of counting the number of colony-forming units and visualization of adhered bacterial cells by scanning electron microscope to evaluate the diamond-like carbon-coated/uncoated samples. The biofilm structure was analyzed by confocal laser scanning microscopy on days 3, 5, 7 and 14 for green fluorescent protein-expressing Pseudomonas aeruginosa. RESULTS: The smooth and carbon-rich structure of the intraluminal diamond-like carbon film remained unchanged after the experiments. The numbers of colony-forming units suggested lower adherence of green fluorescent protein-expressing Pseudomonas aeruginosa and Escherichia coli in the diamond-like carbon-coated samples compared with the uncoated samples. The scanning electron microscope images showed adhered green fluorescent protein-expressing Pseudomonas aeruginosa cells without formation of microcolonies on the diamond-like carbon-coated samples. Finally, biofilm formation on the diamond-like carbon-coated samples was lower until at least day 14 compared with the uncoated samples. CONCLUSIONS: Intraluminal diamond-like carbon coating on a silicone tube has anti-adhesion and anti-biofilm effects. This technology can be applied to urinary catheters made from various materials.

Protective effects of anti-HMGB1 monoclonal antibody on lung ischemia reperfusion injury in mice.

During ischemia reperfusion (IR) injury, high mobility group box 1 (HMGB1), a chromatin binding protein, is released from necrotic cells and triggers inflammatory responses. We assessed the therapeutic effect of a neutralizing anti-HMGB1 monoclonal antibody (mAb) on lung IR injury. A murine hilar clamp model of IR was used, where mice were divided into sham and IR groups with intravenous administration of anti-HMGB 1 mAb or control mAb. We analyzed the effect of anti-HMGB1 mAb against IR injury by assessing lung oxygenation, lung injury score, neutrophil infiltration, expression of proinflammatory cytokines and chemokines, levels of mitogen-activated protein kinase (MAPK) signaling, and measurement of apoptotic cells. Anti-HMGB1 mAb significantly decreased the plasma level of HMGB1 elevated by IR. The severity of IR injury represented by oxygenation capacity, lung injury score, and neutrophil infiltration was significantly improved by anti-HMGB1 mAb treatment. The expression of proinflammatory factors, including IL-1ß, IL-6, IL-12, TNF-α, CXCL-1, and CXCL-2, and phosphorylation of p38 MAPK were both significantly reduced by anti-HMGB1 mAb treatment. Furthermore, anti-HMGB1 mAb treatment suppressed apoptosis, as determined through TUNEL assays. Overall, anti-HMGB1 mAb ameliorated lung IR injury by reducing inflammatory responses and apoptosis. Our findings indicate that anti-HMGB1 mAb has potential for use as a therapeutic to improve IR injury symptoms during lung transplantation.

Outcomes of Right Ventricular Outflow Tract Reconstruction in Children: Retrospective Comparison Between Bovine Jugular Vein and Expanded Polytetrafluoroethylene Conduits.

Bovine jugular vein (BJV) and expanded polytetrafluoroethylene (ePTFE) conduits have been described as alternatives to the homograft for right ventricular outflow tract (RVOT) reconstruction. This study compared RVOT reconstructions using BJV and ePTFE conduits performed in a single institution. The valve functions and outcomes of patients aged < 18 years who underwent primary RVOT reconstruction with a BJV or ePTFE conduit between 2013 and 2017 were retrospectively investigated. 44 patients (20 and 24 with BJV and ePTFE conduits, respectively) met the inclusion criteria. The mean follow-up time was 4.5 ± 1.5 years. No significant differences in peak RVOT velocity (1.8 ± 0.9 m/s vs 2.1 ± 0.9 m/s, P = 0.27), branch pulmonary stenosis (P = 0.50), or pulmonary regurgitation (P = 0.44) were found between the BJV and ePTFE conduit groups, respectively. Aneurysmal dilatation of the conduit was observed in 25.0% of the patients in the BJV conduit group but not in the ePTFE conduit group (P = 0.011). All the cases with aneurysmal dilatation of the BJV conduit were complicated with branch pulmonary stenosis up to 3.0 m/s (P = 0.004). No conduit infections occurred during the follow-up period, and no significant difference in conduit replacement (20.0% vs 8.3%, P = 0.43) was found between the BJV and ePTFE conduit groups, respectively. The outcomes of the RVOT reconstructions with BJV and ePTFE conduits were clinically satisfactory. Aneurysmal dilatation was found in the BJV conduit cases, with branch pulmonary stenosis as the risk factor.

High Mobility Group Box-1 and Blood-Brain Barrier Disruption.

Increasing evidence suggests that inflammatory responses are involved in the progression of brain injuries induced by a diverse range of insults, including ischemia, hemorrhage, trauma, epilepsy, and degenerative diseases. During the processes of inflammation, disruption of the blood-brain barrier (BBB) may play a critical role in the enhancement of inflammatory responses and may initiate brain damage because the BBB constitutes an interface between the brain parenchyma and the bloodstream containing blood cells and plasma. The BBB has a distinct structure compared with those in peripheral tissues: it is composed of vascular endothelial cells with tight junctions, numerous pericytes surrounding endothelial cells, astrocytic endfeet, and a basement membrane structure. Under physiological conditions, the BBB should function as an important element in the neurovascular unit (NVU). High mobility group box-1 (HMGB1), a nonhistone nuclear protein, is ubiquitously expressed in almost all kinds of cells. HMGB1 plays important roles in the maintenance of chromatin structure, the regulation of transcription activity, and DNA repair in nuclei. On the other hand, HMGB1 is considered to be a representative damage-associated molecular pattern (DAMP) because it is translocated and released extracellularly from different types of brain cells, including neurons and glia, contributing to the pathophysiology of many diseases in the central nervous system (CNS). The regulation of HMGB1 release or the neutralization of extracellular HMGB1 produces beneficial effects on brain injuries induced by ischemia, hemorrhage, trauma, epilepsy, and Alzheimer's amyloidpathy in animal models and is associated with improvement of the neurological symptoms. In the present review, we focus on the dynamics of HMGB1 translocation in different disease conditions in the CNS and discuss the functional roles of extracellular HMGB1 in BBB disruption and brain inflammation. There might be common as well as distinct inflammatory processes for each CNS disease. This review will provide novel insights toward an improved understanding of a common pathophysiological process of CNS diseases, namely, BBB disruption mediated by HMGB1. It is proposed that HMGB1 might be an excellent target for the treatment of CNS diseases with BBB disruption.

Cardiosphere-derived exosomal microRNAs for myocardial repair in pediatric dilated cardiomyopathy.

Although cardiosphere-derived cells (CDCs) improve cardiac function and outcomes in patients with single ventricle physiology, little is known about their safety and therapeutic benefit in children with dilated cardiomyopathy (DCM). We aimed to determine the safety and efficacy of CDCs in a porcine model of DCM and translate the preclinical results into this patient population. A swine model of DCM using intracoronary injection of microspheres created cardiac dysfunction. Forty pigs were randomized as preclinical validation of the delivery method and CDC doses, and CDC-secreted exosome (CDCex)-mediated cardiac repair was analyzed. A phase 1 safety cohort enrolled five pediatric patients with DCM and reduced ejection fraction to receive CDC infusion. The primary endpoint was to assess safety, and the secondary outcome measure was change in cardiac function. Improved cardiac function and reduced myocardial fibrosis were noted in animals treated with CDCs compared with placebo. These functional benefits were mediated via CDCex that were highly enriched with proangiogenic and cardioprotective microRNAs (miRNAs), whereas isolated CDCex did not recapitulate these reparative effects. One-year follow-up of safety lead-in stage was completed with favorable profile and preliminary efficacy outcomes. Increased CDCex-derived miR-146a-5p expression was associated with the reduction in myocardial fibrosis via suppression of proinflammatory cytokines and transcripts. Collectively, intracoronary CDC administration is safe and improves cardiac function through CDCex in a porcine model of DCM. The safety lead-in results in patients provide a translational framework for further studies of randomized trials and CDCex-derived miRNAs as potential paracrine mediators underlying this therapeutic strategy.

A new approach to prevent critical cardiac accidents in athletes by real-time electrocardiographic tele-monitoring system: Initial trial in full marathon.

The majority of marathon deaths are caused by sudden cardiac arrest (SCA), which occur in approximately 1 in 57,000 runners. Such deaths are more common among older males and usually occur in the last 4 miles of the racecourse. Although prompt resuscitation, including early use of an automated external defibrillator (AED), improves survival, the deployment of enough trained medical staff and AEDs is difficult due to increased cost. Moreover, most victims of exercise-related SCA have no premonitory symptoms. Therefore, we tried to use a novel approach to prevent sudden cardiac deaths (SCD) related to SCA using real-time electrocardiographic tele-monitoring system, as an initial trial to assess operative possibility in a full marathon. As a result, 3 out of 5 runners had reasonable measurement results and sufficient tele-monitoring without complications related to this trial was possible. However, many investigations and improvements, such as improving cost-effectiveness, reducing noise, and automating the monitoring system, are needed for practical application of these devices for athletes. As a next step, we would establish a novel strategy to reduce SCDs in athletes using next-generation devices, which include an alarm system associated with early application of AED. .

A case of conservative management for left ventricular giant pseudoaneurysm without ST segment changes.

Left ventricular (LV) rupture after myocardial infarction (MI) occasionally results in formation of LV pseudoaneurysm (LVPA) which is prone to rupture because of its thin wall. However, cases of LVPA without ST changes including segment elevation in electrocardiogram (ECG) are rare. In this case, we describe a patient who had relatively mild symptoms and giant LVPA with no specific ECG changes following MI with a confirmed diagnosis via transthoracic echocardiography. Although surgical treatment options are often recommended, conservative therapy was adopted, following which the patient had been well-medicated using antihypertensive drugs and anticoagulants. .

Impact of Cardiac Progenitor Cells on Heart Failure and Survival in Single Ventricle Congenital Heart Disease.

RATIONALE: Intracoronary administration of cardiosphere-derived cells (CDCs) in patients with single ventricles resulted in a short-term improvement in cardiac function. OBJECTIVE: To test the hypothesis that CDC infusion is associated with improved cardiac function and reduced mortality in patients with heart failure. METHODS AND RESULTS: We evaluated the effectiveness of CDCs using an integrated cohort study in 101 patients with single ventricles, including 41 patients who received CDC infusion and 60 controls treated with staged palliation alone. Heart failure with preserved ejection fraction (EF) or reduced EF was stratified by the cardiac function after surgical reconstruction. The main outcome measure was to evaluate the magnitude of improvement in cardiac function and all-cause mortality at 2 years. Animal studies were conducted to clarify the underlying mechanisms of heart failure with preserved EF and heart failure with reduced EF phenotypes. At 2 years, CDC infusion increased ventricular function (stage 2: +8.4±10.0% versus +1.6±6.4%, P=0.03; stage 3: +7.9±7.5% versus -1.1±5.5%, P<0.001) compared with controls. In all available follow-up data, survival did not differ between the 2 groups (log-rank P=0.225), whereas overall patients treated by CDCs had lower incidences of late failure (P=0.022), adverse events (P=0.013), and catheter intervention (P=0.005) compared with controls. CDC infusion was associated with a lower risk of adverse events (hazard ratio, 0.411; 95% CI, 0.179-0.942; P=0.036). Notably, CDC infusion reduced mortality (P=0.038) and late complications (P<0.05) in patients with heart failure with reduced EF but not with heart failure with preserved EF. CDC-treated rats significantly reversed myocardial fibrosis with differential collagen deposition and inflammatory responses between the heart failure phenotypes. CONCLUSIONS: CDC administration in patients with single ventricles showed favorable effects on ventricular function and was associated with reduced late complications except for all-cause mortality after staged procedures. Patients with heart failure with reduced EF but not heart failure with preserved EF treated by CDCs resulted in significant improvement in clinical outcome. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01273857 and NCT01829750.

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.

Decreased Serum Levels of High Mobility Group Box 1 (HMGB-1) after Graft Replacement or Stenting of Abdominal Aortic Aneurysm.

BACKGROUND: High-mobility group box 1 (HMGB-1) is a key substance mediating inflammation and development of atherosclerotic lesions (ALs), including abdominal aortic aneurysms (AAA). Serum levels of HMGB-1 are increased in patients with AAA than those in normal controls because the ALs in AAAs secrete HMGB-1. We therefore postulate that the serum HMGB-1 level should decrease after endovascular aortic repair (EVAR) or open aortic repair (OAR). However, there is no evidence of this in the literature. The purpose of this study was to investigate the changes in HMGB-1 levels after surgical intervention for AAA. We also aimed to determine if the HMGB-1 levels varied between the two procedures. METHODS: Serum HMGB-1 levels were determined in 24 patients with AAA and 25 healthy controls. Twelve of the 24 AAA patients underwent EVAR, whereas the other half underwent OAR. The relationship between HMGB-1 levels and presence of AAA or influence of operative methods on the serum HMGB-1 level were prospectively investigated. RESULTS: Serum HMGB-1 levels in AAA patients were significantly higher than those in healthy controls (9.4 ± 5.7 vs. 4.1 ± 2.0 ng/mL, P < 0.01). The serum HMGB-1 levels in both the EVAR group and the OAR group were significantly decreased from baseline at both 3 mo and 1 y after surgery. CONCLUSIONS: Removal or isolation of AL via surgical intervention significantly decreases serum HMGB-1 levels. The significant postoperative reduction in HMGB-1 levels suggests that important endocrinological changes occur after surgical treatment of AAA.