Kazuhiko Doi

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.

Therapeutic angiogenesis by the controlled release of basic fibroblast growth factor for ischemic limb and heart injury: toward safety and minimal invasiveness.

We review our studies on therapeutic angiogenesis using basic fibroblast growth factor (bFGF) released in a controlled manner from biodegradable gelatin hydrogel (GH). The bFGF-GH was intramuscularly injected in rabbits with limb ischemia. The group treated with bFGF showed an increase in tissue blood flow under laser Doppler imaging and histology showed a greater vascular density compared with controls. Also, bFGF-GH was subepicardially injected into old heart infarcts in rats. In the group treated with bFGF, improved left ventricular function was shown by echocardiography and cardiac catheterization, increased regional blood flow in the peri-infarct area was detected by pinhole single-photon emission computed tomography using 201Tl, and increased vascular density was demonstrated by histology. In rabbits with acute myocardial infarction, the heart was wrapped with the omentum (including the gastroepiploic artery) and a bFGF-GH sheet was applied. Postoperative assessment revealed rich communication from the gastroepiploic artery to the coronary artery and improved cardiac function. The controlled release of bFGF was effective for both limb and heart ischemia and is considered to be suitable for clinical use because its application in animals was feasible and safe with minimal invasiveness.

Enhanced angiogenesis by gelatin hydrogels incorporating basic fibroblast growth factor in rabbit model of hind limb ischemia

Recently we have developed new sustained release system of basic fibroblast growth factor (bFGF) using gelatin hydrogel as a carrier. Using this system, we examined the effect of topical sustained release of bFGF on angiogenesis and tissue blood perfusion in a rabbit model of hind limb ischemia. Thirty-two rabbits underwent excision of right femoral artery under general anesthesia. Two weeks later the rabbits were randomized into four groups (n = 8 each): no treatment, intramuscular injection of gelatin hydrogel alone, and intramuscular injection of gelatin hydrogel incorporating 30 µg and 100 µg of bFGF. Four weeks after each treatment, selective angiography, tissue blood flowmetry using laser Doppler perfusion imaging, and histological examination of thigh muscle were performed. In groups treated with bFGF incorporating gelatin hydrogel, tissue blood flow, number of arterioles, and vascular density were significantly increased in a dose-dependent manner 4 weeks after the treatment. Serum concentrations of bFGF and vascular endothelial growth factor were not elevated 4 weeks after the treatment. In conclusion, sustained release of bFGF using gelatin hydrogel augmented angiogenesis and improved tissue blood flow after excision of the femoral artery.

Gelatin sheet incorporating basic fibroblast growth factor enhances sternal healing after harvesting bilateral internal thoracic arteries

OBJECTIVE We previously reported that a gelatin sheet incorporating basic fibroblast growth factor accelerated sternal healing after bilateral internal thoracic artery removal in normal and diabetic rats. The aim of this study was to evaluate the effects of this therapeutic modality on sternal healing in a large-animal model before performing a clinical trial. METHODS After median sternotomy and bilateral internal thoracic artery removal in a pedicled fashion, 14 beagle dogs received either a gelatin sheet incorporating basic fibroblast growth factor (100 mug per sheet) on the posterior table of the sternum (FGF group, n = 7) or did not receive a gelatin sheet (control, n = 7). We compared sternal healing 4 weeks after surgical intervention between the groups. RESULTS Scintigraphic images obtained by using technetium 99 methylene diphosphonate bone scanning were assessed visually, and the impulse rate was quantified 30 and 60 minutes after injection of technetium 99 methylene diphosphonate to evaluate the sternal perfusion. Sternal uptake was significantly increased in the FGF group (30 minutes: 221% +/- 30% vs 180% +/- 36%; 60 minutes: 267% +/- 26% vs 197% +/- 42%; P <.01). Apparent sternal dehiscence, as assessed radiographically, was observed only in the control animals. Histologically, complete healing of the sternum with marked angiogenesis was observed in the FGF group, whereas poor healing with limited angiogenesis was seen in the control animals. Both bone mineral content (134 +/- 49 vs 52 +/- 32 mg, P <.01) and bone mineral density (133 +/- 53 vs 66 +/- 32 mg/mm(2), P <.05) along the incision line of the sternum, as assessed by means of dual-energy x-ray absorptometry, were higher in the FGF group. CONCLUSIONS A gelatin sheet incorporating basic fibroblast growth factor enhances sternal perfusion and accelerates sternal bone healing in large animals.23

Multislice Computed Tomography Accurately Quantifies Left Atrial Size and Function After the MAZE Procedure

Background— Although the MAZE procedure allows for the recovery of sinus rhythm and left atrial (LA) mechanical function in the great majority of patients with chronic atrial fibrillation (AF), the effects of MAZE on the precise LA geometry and wall motion remain to be elucidated. We hypothesized that LA size and mechanical function in patients with chronic AF and mitral valvular disease are well restored after MAZE. Methods and Results— We studied 14 patients (MAZE group: mean±SD age, 63.9±8.6 years; 8 men and 6 women) who underwent MAZE for chronic AF and mitral valve surgery and 10 patients with sinus rhythm (coronary artery bypass graft [CABG] group: age, 70.0±7.9 years; 5 men and 5 women) who underwent CABG at Takeda Hospital between February 2002 and September 2005. MAZE was conducted by the endocardial application of radiofrequency ablation with a temperature-controlled multipolar radiofrequency catheter. LA volume and booster function were quantitatively evaluated by multislice computed tomography at 17.9±10.0 months (MAZE group) and 15.3±13.6 months (CABG group) postoperatively. All patients with MAZE were free of AF and other atrial arrhythmias during the follow-up period. In the CABG group, LA maximal and minimal volumes and ejection fraction were 109±12 mL, 82±11 mL, and 26±10%, respectively. In the MAZE group, LA maximal volume was 139±17 mL (P=0.187 versus CABG), and LA minimal volume was 121±16 mL (P=0.082 versus CABG), with an ejection fraction of 15±7% (P=0.004 versus CABG). In both groups, all parts of the LA wall contracted toward the geometric center of the LA. The extent of wall motion was significantly worse in the MAZE group compared with the CABG group. In both groups, LA booster function was inversely correlated with LA maximal volume. Conclusions— MAZE with radiofrequency ablation is safe and effective for the restoration of sinus rhythm in patients with chronic AF and mitral valve disease. However, chronic AF associated with mitral valve disease deteriorates LA mechanical function diffusely throughout the LA wall. Further studies with the use of multislice computed tomography are needed to sequentially evaluate LA function after MAZE in patients with and without mitral valve surgery.

Pericardial fluid level of heart-type cytoplasmic fatty acid-binding protein (H-FABP) is an indicator of severe myocardial ischemia

BACKGROUND Heart-type cytoplasmic fatty acid-binding protein (H-FABP) has been reported as a sensitive and specific marker for the early diagnosis of acute myocardial infarction. Our hypothesis was that serum or pericardial fluid levels of H-FABP can reflect not only myocardial infarction but also myocardial ischemia. METHODS A total of 34 patients with unstable angina, who had anginal symptoms and/or ST-changes in ECG monitoring within 24 h before operation, were classified into group A (n=17), and those without these symptoms and changes into group B (n=17). Blood and pericardial fluid samples were obtained immediately after median sternotomy, and serum and pericardial fluid levels of creatine kinase-MB, cardiac troponin-T, and H-FABP were measured. RESULTS Serum H-FABP levels were slightly elevated compared with their normal values in both groups. While they showed no difference between groups A and B (group A vs. B: 8.5+/-1.0 vs. 7.1+/-0.7 ng/ml, P=0.25), pericardial fluid levels of H-FABP were significantly higher in group A than in group B (16.3+/-2.0 vs. 9.6+/-1.0 ng/ml, P=0.0046). H-FABP showed a weak correlation between its serum levels and pericardial fluid levels (r=0.40). CONCLUSIONS Pericardial fluid levels of H-FABP reflect myocardial ischemia occurring within 24 h of their measurements. H-FABP may be secreted into the interstitial space by increased permeability of the myocardial cell membrane associated with severe myocardial ischemia. Thus, pericardial fluid reflects pathophysiological conditions of cardiomyocytes more sensitively than circulating blood.

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.

A potential of autologous pericardium for a sustained-release carrier of vancomycin: a pilot study in vitro.

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Bentall procedure in a patient with severely calcified "porcelain" aorta.

Abstract  Patients with severe calcified “porcelain” aorta carry a high operative risk during cardiac surgery. We report the successful case of Bentall procedure in a patient with severe porcelain aorta. A 65‐year‐old woman was diagnosed with aortic prosthetic valve failure and enlargement of the ascending aorta. Preoperative chest X‐ray and computed tomography scan revealed heavy calcification throughout the aorta. At operation, cardiopulmonary bypass was established through the right axillary artery. The calcified aorta was transected by an oscillating saw under hypothermic circulatory arrest. Distal anastomosis was performed after endarterctomy of the calcified plate, which allowed us to complete the Bentall procedure without the postoperative bleeding.

Mitral valve nonbacterial thrombotic endocarditis: a rare multi-surgery-tolerant survivor of Trousseau’s syndrome

BackgroundFew previous reports have documented cases of nonbacterial thrombotic endocarditis associated with Trousseau’s syndrome for which surgery proved possible for both the primary tumor and the cardiac lesion. The effectiveness of direct oral anticoagulants in patients with Trousseau’s syndrome has also received scant attention.Case presentationA 69-year-old man with repeated episodes of cerebral infarction was diagnosed as having nonbacterial thrombotic endocarditis after mitral valve replacement surgery. Stroke recurred preoperatively under apixaban administration. A stomach biopsy also identified gastric adenocarcinoma, and gastric surgery was performed on the 40th postoperative day. The patient was discharged from the hospital and has been free of thromboembolism under a regime of subcutaneous heparin self-injection thereafter.ConclusionsWe have reported a rare multi-surgery-tolerant survivor of Trousseau’s syndrome in whom subcutaneous heparin injection was useful for preventing thromboembolic events over a long period.