Genichi Sakaguchi

Transplanted Skeletal Myoblasts Can Fully Replace the Infarcted Myocardium When They Survive in the Host in Large Numbers

Background—It is not clear how many skeletal myoblsts (SM) can survive and exert beneficial effects in the host myocardial infarction (MI) area. We assessed the hypothesis that a large number of SM can replace the MI area with reverse left ventricular (LV) remodeling. Methods and Results—MI was created by left coronary artery ligation in male Lewis rats. Four weeks after ligation, 45 rats had skeletal myoblast transplantation in the MI area. They were randomized into 3 groups according to the number of SM: group I (n=15), 5×107; group II (n=15), 5×106; and group III (n=15), 5×105 cells. Donor SM were obtained from neonatal Lewis rats and directly used without expansion. Another four weeks later, all rats were sacrificed following hemodynamic assessment. All heart sections were stained with anti-fast skeletal myosin heavy chain (FSMHC) antibody to determine the spacial extent of donor myocytes. Results—Four weeks after transplantation, LV diastolic dimension was decreased, fractional area change was increased, and MI size was decreased maximally in group I. Histological study showed that donor cells positive for FSMHC occupied the MI area with nearly normal wall thickness in group I, in which estimated volume of donor-derived muscle tissue was 40 mm3. In the other groups, FSMHC-positive cells were found only partly in the MI area. Conclusions—A large number of freshly isolated neonatal SM can survive in the host and fully replace the infarcted myocardium with reverse LV remodeling in rats with MI.

Toward surgical angiogenesis using slow-released basic fibroblast growth factor

OBJECTIVE Therapeutic angiogenesis using basic fibroblast growth factor (bFGF) in coronary artery disease has been documented in a number of papers. However, the effectiveness is discrepant among documents. In this study, we evaluated the distribution of bFGF in the rat heart by different administration methods, and investigated the efficacy of slow-released administration of bFGF using biodegradable hydrogel microspheres (bFGF microspheres) in a pig infarction model toward an enhanced coronary bypass surgery. METHODS Heart failure due to myocardial infarction was induced in rats and pigs. In the rat study, free form of bFGF (central venous injection, intracoronary injection, and intramyocardial administration) and bFGF microspheres (intramyocardial administration) were given 4 weeks later. The remaining radioactivity of bFGF in the hearts was estimated 1, 24, and 72 h later. On the other hand, the pigs were randomized into two groups 4 weeks after myocardial infarction. While the control group (n=8) had gelatin hydrogel microspheres with saline, the FGF group (n=8) received bFGF microspheres in the left ventricular (LV) wall. RESULTS In the rat study, after intramyocardial administration of bFGF microspheres, more bFGF remained in the rat heart 72 h later compared with the other methods (P<0.0001). In the pig study, 4 weeks after the treatment, the FGF group had smaller LV diastolic diameter (48.7+/-5.3 vs. 56.7+/-5.2 mm, P<0.01) than the control group. LV end-systolic elastance was higher in the FGF group (2.96+/-1.2 vs. 1.06+/-0.3 mmHg/ml, P<0.01). In microscopic examinations, many neovessels were found in and around the scar tissue, and the vascular density in the FGF group was significantly higher (61.5+/-18.3 vs. 153.0+/-29.0/mm2, P<0.01). In addition, the infarcted LV walls were less expanded and more thickened in the FGF group. CONCLUSIONS Biodegradable hydrogel microspheres with bFGF improved LV function and inhibited LV remodeling by angiogenesis in pigs with chronic myocardial infarction. bFGF microspheres into ischemic myocardium may revascularize small ungraftable vessels and may potentially increase distal run-off when applied in coronary bypass surgery.

Composite arterial Y graft has less coronary flow reserve than independent grafts.

BACKGROUND It is not known whether a composite Y graft of the left internal thoracic artery can provide sufficient blood flow to the whole left coronary system. The aim of this study was to compare regional myocardial blood flow (MBF) and coronary flow reserve after coronary artery bypass grafting using arterial composite Y graft or independent arterial grafts. METHODS Positron emission tomography was performed at rest and after dipyridamole infusion using oxygen-15-labeled water 2 weeks after coronary artery bypass grafting. Regional MBF was calculated in seven segments of the left ventricle. Coronary flow reserve was defined as the ratio of MBF after dipyridamole infusion to MBF at rest. In the Y graft group (n = 22), a free arterial graft to obtuse marginal arteries was anastomosed to the proximal side of in situ left internal thoracic artery, which was anastomosed to the left anterior descending artery. In the independent graft group (n = 13), left anterior descending and obtuse marginal arteries were independently revascularized using in situ left internal thoracic artery and a free arterial graft. RESULTS There was no difference between the groups in MBF at rest. Coronary flow reserve in the Y graft group was lower than that in the independent group in the anterobasal (1.43 +/- 0.07 versus 1.90 +/- 0.13, p = 0.038), apical (1.24 +/- 0.06 versus 1.64 +/- 0.12, p = 0.003), septal (1.34 +/- 0.05 versus 1.75 +/- 0.13, p = 0.023), and lateral regions (1.19 +/- 0.04 versus 1.66 +/- 0.09, p = 0.001). CONCLUSIONS Although arterial composite Y graft improved MBF at rest, it was not as effective as independent grafts for improving coronary flow reserve soon after coronary artery bypass grafting.

Administration of Control-Released Hepatocyte Growth Factor Enhances the Efficacy of Skeletal Myoblast Transplantation in Rat Infarcted Hearts by Greatly Increasing Both Quantity and Quality of the Graft

Background—We investigated whether simultaneous administration of control-released hepatocyte growth factor (HGF) enhances the efficacy of skeletal myoblast (SM) transplantation (Tx) through its antiapoptotic, angiogenic, and antifibrotic effects in myocardial infarction (MI). Methods and Results—Forty-eight Lewis rats with chronic MI were divided into 4 groups. In Group I (n=14), neonatal SMs (5×106) were transplanted in the MI area with a gelatin sheet incorporating 40 &mgr;g (1 g/L) of HGF applied. Group II (n=14) had SM Tx and placement of a saline sheet. Groups III (n=10) and IV (n=10) had culture medium injection plus HGF and saline sheet application, respectively. Four rats each from Groups I and II were sacrificed at day 1 for TUNEL assay on donor SMs. The percentage of TUNEL-positive donor cells was much lower in Group I than in Group II (P<0.05). At 4 weeks, in Group I, left ventricular diastolic dimension was smallest in echocardiography, end-systolic elastance was highest, and &tgr; was the lowest (both P<0.0005 in ANOVA) in cardiac catheterization. Vascular density inside the graft was higher in Group I than in Group II (P<0.0001). The percentage of fibrotic area inside the graft was smaller in Group I than in Group II (P<0.001). The graft volume as estimated by fast skeletal myosin heavy chain-positive areas was ≈7-fold larger in Group I than in Group II (P<0.0001). Conclusions—In SM Tx, HGF can greatly increase the graft volume and vascularity and reduce fibrosis inside the graft, which enhances the efficacy of SM Tx to infarcted hearts.

Coronary artery bypass surgery is superior to percutaneous coronary intervention with drug-eluting stents for patients with chronic renal failure on hemodialysis.

BACKGROUND Improvements in the results of percutaneous coronary intervention (PCI) with drug-eluting stents (DES) have been extending their use in patients with all forms of coronary artery disease. The purpose of this study was to compare the midterm clinical results of coronary artery bypass surgery (CABG) and PCI with DES in patients with chronic renal failure on hemodialysis. METHODS From January 2002 to December 2006, 29 patients underwent CABG, and 75 patients underwent PCI with DES. For CABG, 24 patients had off-pump surgery. The mean follow-up was 32.0 +/- 22.0 months for CABG and 23.5 +/- 14.8 months for PCI. Survival, cardiac death, major adverse cardiac events (cardiac death, myocardial infarction, revascularization), and target lesion revascularization were analyzed using the Kaplan-Meier method. RESULTS Preoperative characteristics and risk factors were compatible between the groups except for the European System for Cardiac Operative Risk Evaluation (7.3 +/- 2.7 for CABG and 5.0 +/- 2.4 for PCI, p < 0.0001) and the presence of a left main trunk lesion (53.3% for CABG and 18.7% for PCI). Thirty-day mortality was 3.3% for CABG and 4.0% for PCI. The 2-year survival rate was 84.0% for CABG and 67.6% for PCI (p = 0.0271). The cardiac death-free curve at 2 years was 100% for CABG and 84.1% for PCI (p = 0.0122). The major adverse cardiac events-free rate at 2 years was 75.8% for CABG and 31.5% for PCI (p < 0.0001). During the follow-up period, there were 6 late deaths in the CABG group and 27 late deaths (including 6 sudden deaths) in the PCI group. CONCLUSIONS Coronary artery bypass grafting was superior to PCI with DES in patients with chronic renal failure on hemodialysis in terms of long-term outcomes for cardiac death, major adverse cardiac events, and target lesion revascularization. The DES carried a higher risk for sudden death, which might be associated with stent thrombosis.

Surgical Treatment for Postinfarction Left Ventricular Free Wall Rupture

BACKGROUND Left ventricular (LV) free wall rupture is a catastrophic complication after acute myocardial infarction. The optimal therapeutic strategy is controversial and the midterm results are unknown. METHODS Between June 1993 and May 2006, 32 patients with an average age of 73 years (range, from 55 to 96 years) were surgically treated for LV free wall rupture. Sutureless technique (gluing autologous patch to the tear) was applied in all patients. RESULTS The interval between acute myocardial infarction and the rupture was 33 +/- 42 hours and the interval between the rupture and the operation was 3.6 +/- 2.6 hours. Preoperatively, cardiopulmonary resuscitation was performed in eight cases. Percutaneous cardiopulmonary support was placed in six cases and intraaortic balloon pumping in 20 cases preoperatively. The in-hospital mortality was 15.6%. Two patients died of rerupture within ten days. While there was no rerupture during the follow-up period, five patients developed dyskinetic LV aneurysm and one patient developed LV pseudoaneurysm. CONCLUSIONS The sutureless technique is a simple and effective option for the surgical treatment for LV free wall rupture. The preoperative moribund condition was highly associated with the operative mortality.

A pig model of chronic heart failure by intracoronary embolization with gelatin sponge

BACKGROUND We produced a large-animal model of left ventricular (LV) failure induced by transcatheter embolization of the left coronary artery using a gelatin sponge. METHODS Fourteen male pigs underwent transcatheter embolization of the left anterior descending artery (LAD) using gelatin sponge to produce anteroapical myocardial infarction. Coronary angiography was performed 1 week after the coronary embolization. The animals were followed up with echocardiography and LV pressure-volume study for the subsequent 8 weeks, and the data were compared with those of the control group (n = 13). RESULTS The procedure mortality was 2 of 14 (14%). Coronary angiography revealed the occluded LAD was recanalized with poor run-off. The LV end-diastolic dimension progressively increased (control versus myocardial infarction: 39 +/- 2 mm versus 49 +/- 4 mm, p < 0.001 at week 4; and 40 +/- 2 mm versus 57 +/- 6 mm, p < 0.001 at week 8). Fractional area change decreased over 8 weeks (77% +/- 10% versus 43% +/- 6%, p < 0.001 at week 4; and 77% +/- 10% versus 40% +/- 8%, p < 0.001 at week 8). End-systolic elastance progressively decreased over 8 weeks (3.04 +/- 0.73 mm Hg/mL versus 1.54 +/- 0.51 mm Hg/mL, p < 0.0001 at week 4; and 2.88 +/- 0.44 mm Hg/mL versus 1.05 +/- 0.21 mm Hg/mL, p < 0.001 at week 8). The plasma levels of brain natriuretic peptide were significantly higher in the study group (543 +/- 131 pg/mL versus 1,321 +/- 364 pg/mL, p < 0.001 at week 4; and 610 +/- 152 pg/mL versus 1,523 +/- 232 pg/mL, p < 0.001 at week 8). CONCLUSIONS This pig model of chronic heart failure is reliable, reproducible, and amenable to investigate other surgical procedures.

Preoperative evaluation of patients with liver cirrhosis undergoing open heart surgery

ObjectiveClinical outcomes after open heart surgery in patients with liver cirrhosis are not satisfactory. For evaluating hepatic function, the Child-Pugh classification has been widely used. It has been reported that open heart surgery can be performed safely in patients with mild liver cirrhosis. In this study, we examined the clinical outcomes after open heart surgery in patients with liver cirrhosis and evaluated the usefulness of the Child-Pugh classification.MethodsThere were 12 liver cirrhosis patients who underwent open heart surgery between January 2002 and December 2006 at our institution. The severity of cirrhosis was graded according to the Child-Pugh classification. We reviewed clinical outcomes, such as postoperative mortality and morbidity, and tried to determine the risk factors. Finally, we assessed the usefulness of the Child-Pugh classification.ResultsSix patients were classified as having Child class A, and the other six patients were classified as B. The overall mortality of group A was 50%, and that of group B was 17%. Postoperative major morbidities occurred in half of the patients of Child class A and in all of the patients of Child class B. Patients who experienced major morbidities had markedly lower levels of serum cholinesterase (106 ± 46 vs. 199 ± 72 IU/l; P = 0.02) and lower platelet level (7.5 ± 2.9 vs. 11.9 ± 3.6 × 104/μl; P = 0.04).ConclusionThe mortality and morbidity rates were high even in the Child class A patients. The Child classification may be an insufficient method for evaluating hepatic function. We have to assess other factors, such as the serum cholinesterase level or the platelet count.

Haptic reproduction and interactive visualization of a beating heart for cardiovascular surgery simulation

This paper aims to achieve haptic reproduction and real-time visualization of a beating heart for cardiac surgery simulation. Unlike most forgoing approaches, the authors focus on time series datasets and propose a new framework for interactive simulation of active tissues. The framework handles both detection and response of collisions between a manipulator and a beating virtual heart. Physics-based force feedback of autonomous cardiac motion is also produced based on a stress-pressure model, which is adapted to elastic objects filled with fluid. Time series datasets of an adult man were applied to an integrated simulation system with a force feedback device. The system displays multi-dimensional representation of a beating heart and provides a basic training environment for surgical palpation. Finally, results of measurement and medical assessment confirm the achieved quality and performance of the presented framework.

Increased pericardial fluid concentrations of the mature form of adrenomedullin in patients with cardiac remodelling

Background: There is evidence that adrenomedullin has autocrine or paracrine activities that oppose cardiac remodelling. However, it remains unclear whether it exerts those local functions in heart failure patients. Objective: To investigate the relation between plasma and pericardial fluid concentrations of adrenomedullin and left ventricular haemodynamic variables. Design: Samples of plasma and pericardial fluid were obtained from 50 patients undergoing cardiac surgery. They were classified into two groups: group N (n = 27) with a left ventricular end diastolic volume index (LVEDVI) ≤ 90 ml/m2; and group R (n = 23) with LVEDVI > 90 ml/m2. Plasma and pericardial fluid concentrations of total adrenomedullin (tAM) and mature adrenomedullin (mAM) were measured and related to the preoperative haemodynamic variables. Results: Pericardial fluid concentrations of mAM were much higher than the plasma concentration in both group N and group R (mean (SEM), 10.6 (1.7) v 3.3 (0.2) fmol/ml, p = 0.0001; and 21.2 (2.8) v 3.9 (0.3) fmol/ml, p < 0.0001, respectively). The ratio mAM/tAM in pericardial fluid was significantly higher than in plasma (0.56 (0.02) v 0.28 (0.02), p < 0.0001). Pericardial fluid concentrations of mAM, but not plasma concentrations, were significantly correlated with LVEDVI, left ventricular end systolic volume index, left ventricular ejection fraction, and left ventricular mass index (r = 0.60, 0.63, −0.54, and 0.47, respectively). Conclusions: Raised pericardial fluid concentrations of mAM may reflect the actions of adrenomedullin as a local mediator against cardiac remodelling in patients with left ventricular dysfunction.