Nobuhisa Ohno

Inhibition of Rho-Associated Kinase Results in Suppression of Neointimal Formation of Balloon-Injured Arteries

BACKGROUND Rho-associated kinase (ROCK), an effector of small GTPase Rho, regulates vascular tone via a calcium sensitization mechanism and plays a key role in the pathogenesis of hypertension. However, its role in vascular growth remains unclear. METHODS AND RESULTS Y-27632, a specific ROCK inhibitor, and the overexpression of dominant-negative ROCK suppressed the mitogen-induced DNA synthesis of cultured vascular smooth muscle cells (VSMCs), which indicates the essential role of ROCK in the control of VSMC proliferation in vitro. Y-27632 also suppressed the chemotaxis of VSMCs. Male Wistar rats were systemically given Y-27632 (35 to 70 mg. kg(-1). day(-1)) through an intraperitoneal infusion. The neointimal formation of balloon-injured carotid arteries was significantly suppressed in Y-27632-treated rats (intima/media ratio, 0.22+/-0.02) compared with vehicle-treated rats (intima/media ratio, 0.92+/-0.21) or hydralazine-treated rats with a similar blood pressure decrease (intima/media ratio, 1.03+/-0.15). The phosphorylation of myosin phosphatase and myosin light chain was elevated in injured arteries in a Y-27632-sensitive manner, indicating the augmentation of ROCK activity in neointimal formation. The downregulation of the cyclin-dependent kinase inhibitor p27(kip1) in injured vessels was reversed by Y-27632 treatment, reflecting the antiproliferative effect of ROCK inhibition in vivo. CONCLUSIONS We conclude that ROCK plays a key role in the process of neointimal formation after balloon injury. Thus, the inhibition of ROCK may be a potential therapeutic strategy for treating vascular proliferative disorders and hypertension.

Accelerated Reendothelialization With Suppressed Thrombogenic Property and Neointimal Hyperplasia of Rabbit Jugular Vein Grafts by Adenovirus-Mediated Gene Transfer of C-Type Natriuretic Peptide

Background—Vein graft disease limits the late results of coronary revascularization. C-type natriuretic peptide (CNP) inhibits the growth of vascular smooth muscle cells. Given the effects of CNP on cGMP cascade, we hypothesized that transfected CNP genes modulate endothelial repair and thrombogenicity in the vein graft. Methods and Results—Autologous rabbit jugular vein grafts were incubated ex vivo in a solution of adenovirus vectors containing CNP gene (Ad.CNP) or Escherichia coli lac Z gene (Ad.LacZ) and then interposed in the carotid artery. Reendothelialization, mural thrombi formation, and intima/media ratio were evaluated on the 14th and 28th postoperative days. More reendothelialization was seen in Ad.CNP-infected grafts than in Ad.LacZ-infected grafts both at 14 days (0.81±0.05 versus 0.30±0.14, P <0.01) and at 28 days (0.96±0.01 versus 0.45±0.08, P <0.001). The mural thrombus area was smaller in Ad.CNP-infected grafts than in Ad.LacZ-infected grafts. Neointimal thickening was significantly suppressed in the Ad.CNP group. The in vitro wound assay with human coronary artery endothelial cells revealed significant potentiation of the wound repair process by CNP and atrial natriuretic peptide administration. Conclusions—Infected Ad.CNP accelerated reendothelialization and suppressed thrombosis and neointimal hyperplasia. The method may potentially prevent vein graft disease in patients undergoing coronary artery revascularization.

Objective assessment of CNS function within 6 hours of spinal cord ischemia in rabbits

PurposeTo develop a neurologic scoring (NS) system to objectively assess CNS function shortly after spinal cord ischemia.MethodsSpinal cord ischemia was induced by temporarily clamping the infrarenal aorta in 27 rabbits anesthetized with isoflurane/N2O/O2 without muscle relaxants. Animals were divided ito group I, normothermic ischemia [I-a, 11 min (n=8); I-b, 12 min (n=8)], and group II, 60 min hypothermic ischemia targeted to II-a, 29.5°C (n=5), and II-i, 30.0°C (n=6). Postischemic neurologic function was scored from 0 to 6.ResultsSeventy-five percent of each group I subgroup ended with paraplegia. Function in the I-b group tended to be worse than in I-a (NS=1.7vs 1.9P>0.05). Hypothermia of 29.9±0.1°C protected partially (NS=2.8), whereas 29.4±0.1°C resulted in significantly higher NS, starting at 150 min (P<0.05vs IIi) with total recovery 5.5 hours (P<0.0001) post re-perfusion.ConclusionsProtection of the spinal cord from ischemia can be objectively quantitated by our system. Protection strategies can be compared within 6 h of the ischemia-insult.

Taurine Potentiates the Efficacy of Hypothermia

To assess the protective effect of exogenous taurine on the central nervous system, spinal cord ischemia was induced for 60 minutes in 16 rabbits randomized into 3 groups. Group 1 (n = 5) had hypothermia targeted to 30.5°C and 10 mmol·kg−1 taurine, group 2 (n = 5) had hypothermia targeted to 29.5°C, and group 3 (n = 6) had hypothermia targeted to 30°C. Group 1 was cooled to 30.6 ± 0.07°C and group 2 was cooled to 29.4 ± 0.07°C; both had total functional recovery (rabbits able to keep normal posture, to walk, and to hop) within 6 hours of reperfusion. None of the group 3 animals that were cooled to 29.9 ± 0.05°C recovered function. It was concluded that taurine combined with hypothermia protected the spinal cord from 60 minutes of ischemia at a temperature that could not otherwise ensure protection. The protective effect contributed by taurine was equivalent to 1.2°C.

Pathologic aspects of polytetrafluoroethylene sutures in human heart

BACKGROUND Polytetrafluoroethylene (PTFE) sutures have been widely used as a mitral chord substitute. We present the cases of 4 patients who underwent mitral valve repair with chordal replacement by PTFE sutures and these required another operation. This gave us the chance to examine the PTFE sutures. METHODS Structural analysis of the PTFE sutures was performed 26 to 378 days postoperatively. The specimens were examined grossly, microscopically, and by scanning or transmission electron microscopy or both. RESULTS The PTFE suture in 1 patient was found to be completely covered with endothelial cells 154 days postoperatively. There was no calcification, and the flexibility and pliability of the PTFE sutures was preserved. Even though the PTFE sutures seemed uncovered on visual inspection, there was a thin lining of collagen and fibrin on the surface. Endothelial cells were seen in areas that looked clear in one specimen 26 days postoperatively. CONCLUSIONS We think that the new layer of collagen could be promising in terms of durability and that the endothelial layer wil resemble normal tissue in its anticoagulant properties.

Cell transplantation in non-ischemic dilated cardiomyopathy. A novel biological approach for ventricular restoration.

OBJECTIVE With a rising incidence, dilated cardiomyopathy (DCM) is regarded as a major health care concern. Although both medical therapy and novel surgical treatments have been applied to treat DCM, the effects of preventing left ventricular (LV) dilatation are limited, and the mortality rate associated with the disease remains high. Thus novel management strategies for improved treatment of DCM are awaited. METHODS Researchers have found that, in models of regional ventricular dysfunction, transplanted cells induced a profound biological phenomenon that restored contractile function and prevented ventricular dilatation. We have investigated muscle cell transplantation in hamsters with DCM, and have found that heart cells and smooth muscle cells survived in the host myocardium after transplantation, which suppressed LV dilatation and wall thinning, and preserved heart function. Our current studies are focusing on the clinical applicability of these encouraging early findings by evaluating the optimal cell types, the timing of transplantation, and cryopreservation as cell storage. Concurrently, we are investigating the influence of cell transplantation on myocardial remodeling in order to outline the mechanism of benefit afforded by donor cell engraftment. We believe that the timing of cell transplantation with respect to the progression of the underlying disease is critical in preventing ventricular thinning, dilation and preserving cardiac function. CONCLUSIONS This novel approach can be a clinically applicable biological therapy for patients with progressive DCM. More studies to uncover the specific molecular and cellular effects of cell transplantation on the host myocardium are necessary for future clinical application.

Open stent-grafting for adult patent ductus arteriosus with a distal aortic arch aneurysm

Closure of adult patent ductus arteriosus (PDA) is difficult for its variation. We report a case of open stent-grafting for a 67-year-old woman who had PDA and a concomitant distal aortic arch aneurysm. The pulmonary/systemic flow ratio was 1.88, and the pulmonary arterial pressure was 34/21(25). The operation was done through a median sternotomy under hypothermic cardioplegic arrest. We opened the anterior wall of the arch just distal to the left subclavian artery and placed a stent-graft into the descending aorta. At 5 months after discharge, three-dimensional computed tomography showsed disappearance of PDA and no endoleak of the stent-graft.

Severe Aortic Valve Regurgitation Due to Takayasu's Aortoarteritis in a Child

An 8-year-old Japanese boy with severe aortic valve regurgitation was treated by the Ross procedure with use of the full root technique. Takayasus aortoarteritis was diagnosed 2 months after the operation. At 8 months after the operation, follow-up echocardiography revealed an aortic root pseudoaneurysm, which was surgically repaired. At 24 months after operation, the patient continues to receive prednisolone, azathioprine, and cyclophosphamide and is in good health, with good pulmonary autograft function.

Truncal valve repair using autologous pericardial patch augmentation

A 35-month-old boy with severe truncal valve regurgitation underwent successful repair by tricuspidization using raphe slicing and an extension technique with glutaraldehyde-treated autologous pericardium. His truncal valve regurgitation improved from severe to mild 5 years postoperatively. Tricuspidization using raphe slicing and valve extension with autologous pericardium might be one of the alternatives for truncal valve regurgitation with a quadricuspid valve.

Early Stent Graft Perforation after Endovascular Repair for Pseudoaneurysm That Was Associated with Clavicle Nonunion.

We report the case of a 62-year-old man who experienced a left axillary artery pseudoaneurysm that was secondary to nonunion of a 30-year-old left midshaft clavicle fracture. He initially underwent endovascular repair using a self-expanding nitinol stent graft, which was perforated at postoperative day 5. Therefore, we performed open repair with concomitant clavicle resection, and no complications were observed during an approximately 6-year follow-up. We recommend performing clavicle resection with vascular repair to prevent recurrence in similar cases.