Masaaki Yamagishi

Controlled Delivery of Basic Fibroblast Growth Factor Promotes Human Cardiosphere-Derived Cell Engraftment to Enhance Cardiac Repair for Chronic Myocardial Infarction

OBJECTIVES This study was designed to determine whether controlled release of basic fibroblast growth factor (bFGF) might improve human cardiosphere-derived cell (hCDC) therapy in a pig model of chronic myocardial infarction. BACKGROUND Current cell therapies for cardiac repair are limited by loss of the transplanted cells and poor differentiation. METHODS We conducted 2 randomized, placebo-controlled studies in immunosuppressed pigs with anterior myocardial infarctions. Four weeks after coronary reperfusion, 14 pigs were randomly assigned to receive an intramyocardial injection of placebo medium with or without bFGF-incorporating hydrogel implantation. As a second study, 26 pigs were randomized to receive controlled release of bFGF combined with or without hCDCs or bone marrow-derived mesenchymal stem cell transplantation 4 weeks after reperfusion. RESULTS Controlled release of bFGF in ischemic myocardium significantly augmented the formation of microvascular networks to enhance myocardial perfusion and contractile function. When combined with cell transplantation, the additive effects of bFGF were confined to hCDC-injected animals, but were not observed in animals receiving human bone marrow-derived mesenchymal stem cell transplantation. This was shown by increased donor-cell engraftment and enhanced cardiomyocyte differentiation in the transplanted hearts, resulting in synergistically improved ventricular function and regional wall motion and reduced infarct size. CONCLUSIONS Controlled delivery of bFGF modulates the post-ischemic microenvironment to enhance hCDC engraftment and differentiation. This novel strategy demonstrates significant functional improvements after myocardial infarction and may potentially represent a therapeutic approach to be studied in a clinical trial in human heart failure.

Experimental scoliosis in melatonin‐deficient C57BL/6J mice without pinealectomy

Abstract:  The etiology of idiopathic scoliosis is unknown. Scoliosis with many characteristics closely resembling those seen in idiopathic scoliosis has been produced in young chickens and bipedal rats after pinealectomy. In this study, we induced experimental scoliosis in C57BL/6J mice without pinealectomy and melatonin treatment suppressed the development of scoliosis. A total of 100 mice were divided into four groups: 20 quadrupedal mice served as controls; 30 mice underwent resection of two forelegs and tail at 3 wk of age (bipedal mice); the remaining 20 quadrupedal and 30 bipedal mice received intraperitoneal melatonin (8 mg/kg BW) at 19:00 hr daily. Before killing, blood samples were collected in the middle of dark cycle and melatonin levels were measured by radioimmunoassay. Spine X‐ray and helical 3D‐CT were examined after killing at 5 months of age. The bipedal mice without a tail were able to walk with standing posture, whereas the quadrupedal mice did not walk with standing posture. In C57BL/6J mice, the serum melatonin was reduced to nearly zero; however, the normal level was restored in both bipedal and quadrupedal mice after the injection of melatonin. Scoliosis with rib humps developed in 29 of 30 bipedal and in five quadrupedal mice. None of mice with melatonin treatment developed scoliosis. The results suggest that melatonin deficiency in bipedal mice appears to play crucial role for development of scoliosis. Also the restoration of melatonin levels prevents the development of scoliosis.

Simulative operation on congenital heart disease using rubber-like urethane stereolithographic biomodels based on 3D datasets of multislice computed tomography

OBJECTIVE Stereolithographic biomodelling is a technique where photosensitive liquid resin is polymerised with a pinpoint laser beam controlled by three-dimensional (3D) datasets. This study was designed to assess whether a stereolithographic biomodelling technique is applicable for precise anatomical diagnosis and simulation surgery of complicated congenital heart disease. METHODS Twelve stereolithographic biomodels were manufactured with multislice computed tomography (MSCT)-based 3D datasets. They were made of photosensitive liquid epoxy or urethane. RESULTS All the solid epoxy and rubber-like urethane biomodels reproduced the complex anatomical structures of the arteries and veins in congenital heart diseases. Furthermore, the rubber-like urethane biomodels allowed the surgeon to cut and suture, thus facilitating the simulation of the surgical operation. CONCLUSIONS Stereolithographic biomodelling is a promising technique for the preoperative practice and simulation of individual surgery. This technique would be useful in the planning of novel and innovative surgical procedures of congenital heart disease.

Expanded polytetrafluoroethylene conduits and patches with bulging sinuses and fan-shaped valves in right ventricular outflow tract reconstruction: Multicenter study in Japan

OBJECTIVE There is no optimal substitute for right ventricular outflow tract (RVOT) reconstruction in congenital heart defects. Expanded polytetrafluoroethylene (ePTFE) valved conduits and patches may be a good alternative to homografts and bovine jugular veins. We have developed a fan-shaped ePTFE valve and an ePTFE valved conduit and patch with bulging sinuses with the aim of enhancing the long-term valve function. METHOD Bulging sinuses were constructed on ePTFE conduits and patches as described previously (J Thorac Cardiovasc Surg. 2007;134:327-32). Between February 2001 and January 2011, 794 patients (aged 14 days to 56.8 years old; median, 2.0 years old) had ePTFE valves implanted for RVOT reconstruction at 52 Japanese institutes. Conduits with a fan-shaped ePTFE valve were implanted in 325 patients and a patch with a fan-shaped ePTFE valve was implanted in 469 patients. Valve function was assessed by a series of echocardiograms postoperatively. RESULTS The mean follow-up was 3.6 years (1.1 months to 10.0 years). Freedom from reoperation at 10 years was 95.4% in patients with conduits and 92.3% in those with patches. Pulmonary insufficiency was mild or nonexistent in 95.0% of patients with conduits and 79.6% of patients with patches. The pressure gradient between the right ventricle and the pulmonary artery was 14.0 ± 13.2 mm Hg in patients with conduits and 11.6 ± 11.6 mm Hg in patients with patches. CONCLUSIONS Fan-shaped ePTFE valved conduits and patches with bulging sinuses have a high freedom from reoperation and prevent pulmonary insufficiency. They represent a promising material for RVOT reconstruction.

Hedgehog signaling: a biophysical or biomechanical modulator in embryonic development?

Abstract:  Although embryonic development is inevitably affected by biophysical or biomechanical processes, it has yet to be elucidated to what extent molecular mechanisms of development are modulated by such physical factors. The hedgehog family, including Sonic hedgehog (Shh), is the most well‐known morphogens involved in the developmental pattern formation of various organs, such as the nervous system, face, limbs, and skin appendages. There are several unique features in hedgehog signaling including long‐range diffusion or positive and negative feedback loops, suggesting the possible modification of hedgehog signaling by biophysical or biomechanical factors. Especially, the period of embryonic day 8–10 is characterized by various biomechanically regulated processes in mouse development, such as axial rotation and vasculoangiogenesis. We executed a series of experiments using a mouse whole embryo culture system to investigate the biomechanical roles of hedgehog signaling during this period. In this review, we examine various examples in which biophysical and biomechanical aspects of hedgehog signaling in development are revealed, including our own data using the mouse whole embryo culture system.

Total cavopulmonary connection without the use of prosthetic material: Technical considerations and hemodynamic consequences

Total cavopulmonary connection with use of an autogenous intraatrial tunnel to create a straight tube between the inferior vena cava and the pulmonary artery was attempted in several types of cardiac anomaly in eight consecutive candidates for the Fontan operation. A small right atrium with an extraordinary location of the inferior vena cava and a short superior vena cava prevented the use of this procedure in two cases. By preserving the crista terminalis and the sinus node and its arteries we prevented the development of postoperative atrial arrhythmias in the short follow-up period, and the P trigger-signal averaged P waves were not different from those of other cardiac anomalies. The proximal stump of the superior vena cava was not incised in any case to enlarge the anastomosis, even when size mismatch between the superior and inferior venae cavae existed, as in a case of bilateral superior venae cavae. Stretching the vessels by approximately 150% was possible and permitted an adequate anastomosis. Cavopulmonary connections via the intraatrial tunnel ensured smooth, nonturbulent, somewhat pulsatile flow without a pressure gradient. We concluded that the creation of an autogenous intraatrial tunnel was possible in many cases without serious complications and that this procedure has potential benefit for the pulmonary circulation in the aspect of pulsatility.

Effects of controlled perioperative antimicrobial prophylaxis on infectious outcomes in pediatric cardiac surgery.

Objectives:To examine the efficacy of a protocol for the prophylactic use of antimicrobials in pediatric cardiac surgery. Design:Nonrandomized comparison of two groups of patients studied sequentially. Setting:Pediatric intensive care unit of university hospital. Patients:Infants and children <18 yrs of age who had undergone cardiac surgery. Interventions:Limitation of prophylactic antimicrobials to <48 hrs after operation and, in patients at high risk of methicillin-resistant Staphylococcus aureus, strong recommendation to use glycopeptides. Measurements and Main Results:No intervention was applied in 189 patients (control group) during the first 21 months, whereas the intervention was applied in 185 patients (intervention group) during the next 18 months. In the intervention group, prophylaxis was recommended to be discontinued <48 hrs postoperatively. As a result, antimicrobials were administered for a median of 4 days (range 2–14) in the intervention group, significantly shorter than 7 days (3–35) in controls. This was associated with a trend toward a lower frequency of postoperative infections, including at the surgical site, and with significantly lower costs of antimicrobial therapy and a significantly lower rate of newly acquired nasal colonization with antibiotic-resistant pathogens in the intervention group (8%) than in controls (17%).Since, in the intervention group, glycopeptides were strongly recommended for patients at high risk of methicillin-resistant S. aureus, the frequency of surgical-site infections (0% vs. 18%) and the frequency of all infections (11% vs. 39%) were significantly lower in the intervention group than in the control group. Conclusions:Limiting the duration of prophylactic antimicrobials was cost-effective and reduced the risk of acquiring resistant pathogens without increasing the frequency of postoperative infections. The use of glycopeptides in properly selected patients at high risk of methicillin-resistant S. aureus infection can lower the risk of postoperative infections.

Defects in aortic fusion and craniofacial vasculature in the holoprosencephalic mouse embryo under inhibition of sonic hedgehog signaling.

Sonic hedgehog (Shh) is a well-known morphogen indispensable in facial and nervous development, and recently it has also garnered much attention as a potent angiogenic factor. We previously created an animal model of holoprosencephaly by administration of cyclopamine, a specific inhibitor of hedgehog signaling, to the mouse embryos cultured in vitro, and found several types of angiogenic defects. In this study, we focused on other angiogenic phenotypes in the same model. When cyclopamine was added for embryonic day (E) 8.0-9.5, a pair of immature dorsal aortae, which normally fuse to form the single aorta by E9.5, remained to be separated. Expressions of vascular endothelial growth factor and bone morphogenetic protein 4, putative mediators of aortic fusion, were also reduced around the aorta by blockade of Shh signaling. When cyclopamine was added for E8.5-10.5, vessels on the surface of craniofacial region (possibly external cardinal veins) were extended and malformed. These results suggest that Shh signaling is essential for some aspects of embryonic angiogenesis, and that pathophysiology of holoprosencephaly may involve, at least in part, the Shh-dependent angiogenesis.

Surgical treatment of Charcot spine.

The authors report 4 cases of Charcot spine treated surgically. In the surgical treatment, combined anterior and posterior with extensive debridement, autogenous bone grafting, and posterior instrumentation is the main therapeutic modality. Some cases with mild bone destruction could be treated by posterior interbody fusion. For the unstable, symptomatic Charcot spine, surgical treatment can provide excellent results.

Bioelectrical impedance analysis for assessment of severity of illness in pediatric patients after heart surgery

OBJECTIVE To investigate whether perioperative changes in bioelectrical impedance reflect the severity of illness in pediatric patients after heart surgery. DESIGN Prospective, controlled study. SETTING University-affiliated childrens hospital. PATIENTS A total of 107 patients admitted to a pediatric intensive care unit after congenital heart surgery. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Single frequency (50 kHz) bioelectrical impedance was measured in the lower extremities before surgery and immediately, 16 hrs, and 40 hrs after admission (D0, D1, D2) to the pediatric intensive care unit. Postoperative changes in bioelectrical impedance were assessed by calculating values relative to the preoperative data (bioelectrical impedance ratio). These bioelectrical impedance ratios at D0 in both the nonsurviving and surviving patients were 0.84 +/- 0.06 and 0.85 +/- 0.01 (mean +/- SE), respectively, indicating that the initial decrease caused by surgical stress itself was not directly related to the prognosis. The bioelectrical impedance ratio showed an increase toward preoperative values in surviving patients (0.94 +/- 0.02) at D1, and they showed a sustained decrease (0.70 +/- 0.06) in nonsurviving patients. Patients with a bioelectrical impedance ratio at D1 of < 0.8 showed a higher mortality (25%) compared with those patients with a day-1 bioelectrical impedance ratio of > or = 1.0 (0%). The duration of the stay in the pediatric intensive care unit, mechanical ventilation, and inotropic support were all significantly longer in the patients with the lower bioelectrical impedance ratio. CONCLUSIONS Measurement of the relative changes in postoperative bioelectrical impedance, which reflects perioperative alterations in body composition, provides a quantitative estimation of the critical illness in pediatric patients after heart surgery.