Kazuaki Kataoka

Intramyocardial sustained delivery of basic fibroblast growth factor improves angiogenesis and ventricular function in a rat infarct model

Abstract Recently we have demonstrated that the release of basic fibroblast growth factor (bFGF) from a biodegradable gelatin hydrogel carrier depends on the degradation of hydrogel in vivo. The purpose of our study was to assess whether bFGF-incorporating gelatin hydrogels induce myocardial angiogenesis and improve left ventricular function in the infarcted myocardium of rats. Studies were conducted in 22 Lewis rats after a 4-week ligation of the proximal left anterior descending coronary artery. The rats were randomized into the following two groups: the control group (n = 11) had an intramyocardial injection of saline alone, and the FGF group (n = 11) had gelatin hydrogel microspheres containing 100 μg of bFGF injected into the border zone of the infarct area after the repeat left thoracotomy. For visualization of the regional myocardial blood flow in the rat heart, 201Tl images were taken just before and 4 weeks after the treatment using a 4-head single photon emission computed tomography scanner with pinhole collimators. Left ventricular function was also assessed with echocardiography and a micromanometer-tipped catheter. Finally, the extent of myocardial angiogenesis was evaluated quantitatively in the postmortem analysis. The 201Tl defect score in the control group remained unchanged before and after the treatment, whereas it decreased significantly in the FGF group. Both regional and global left ventricular function was significantly better in the FGF group compared with the control group. The vascular density in the border zone of the infarct in the FGF group was significantly higher than that in the control group. In conclusion, intramyocardial injection of bFGF-impregnated gelatin hydrogels induces functionally significant angiogenesis and improves left ventricular systolic and diastolic function in the infarcted myocardium of rats.

Measuring serum aminoterminal type III procollagen peptide, 7S domain of type IV collagen, and cardiac troponin T in patients with idiopathic dilated cardiomyopathy and secondary cardiomyopathy

Objective To identify new prognostic indicators in idiopathic dilated cardiomyopathy (DCM) and secondary cardiomyopathy. Design and patients Serum concentrations of aminoterminal propeptides of type III procollagen and the 7S domain of type IV collagen (7S collagen)—which have recently been used as indicators of collagen matrix turnover in other diseases—and of cardiac troponin T were measured in 17 consecutive patients with DCM and in four patients with secondary cardiomyopathy (one associated with hyperthyroidism, two with chronic renal failure, one with amyloidosis), confirmed by endomyocardial biopsy. The correlation of these variables with short term prognosis was then assessed prospectively. Results 11 of the patients were positive for type III procollagen, 7S collagen, or troponin T even though their creatine kinase concentrations were within the normal range. These patients had a poor short term prognosis (p < 0.001). Conclusions Within the DCM and secondary cardiomyopathy groups, there was a subgroup of patients with raised concentrations of serum collagen and troponin T, for whom short term prognosis was poor. Although it is unclear whether these serum peptide levels reflect ongoing myocyte degeneration and interstitial fibrosis, they may serve as useful new prognostic indicators for cardiomyopathy.

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

LOX-1 pathway affects the extent of myocardial ischemia-reperfusion injury

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) was originally identified as a receptor for oxidized low-density lipoprotein predominantly expressed in endothelial cells. LOX-1 expression can be induced in cardiomyocytes and that activation of LOX-1 is involved in apoptosis. To investigate possible roles of LOX-1 in myocardial ischemia-reperfusion injury, rats were subjected to coronary artery ligation for 1h followed by reperfusion for 2h. Immunohistochemistry revealed that expression of LOX-1 in cardiac myocytes was induced following ischemia-reperfusion but not ischemia alone. Administration of anti-LOX-1 monoclonal antibody resulted in a nearly 50% reduction in myocardial infarction size compared with that of normal IgG or saline (P<0.05). These findings suggest that activation of the LOX-1 pathway is involved in determining the extent of myocardial ischemia-reperfusion injury and that inhibition of the LOX-1 pathway may provide a novel strategy for treatment of acute myocardial infarction in humans.

Detection of Postischemic Regional Left Ventricular Delayed Outward Wall Motion or Diastolic Stunning After Exercise-induced Ischemia in Patients with Stable Effort Angina by Using Color Kinesis

To determine whether postischemic diastolic stunning could be detected using color kinesis, we evaluated regional left ventricular (LV) diastolic wall motion in 36 patients with stable effort angina and a coronary stenosis (> or = 70% of luminal diameter), and in 30 control subjects. Regional LV filling fraction in the short-axis view during the first 30% of the LV filling time (color kinesis diastolic index) was determined before, 20 minutes, 1 hour, and 24 hours after the treadmill exercise test. In 33 of the 36 patients (92%), new regional LV delayed outward motion during early diastole (color kinesis diastolic index < or = 40%) was detected at 20 minutes after exercise. The regional LV delayed diastolic wall motion showed significant improvement but persisted 1 hour afterward in 20 of 36 patients (56%), and disappeared 24 hours after exercise. Detection of regional stunned myocardium with impaired diastolic function may be a useful tool for the diagnosis of coronary artery disease.

Biodegradable polymer-based, argatroban-eluting, cobalt-chromium stent (JF-04) for treatment of native coronary lesions: final results of the first-in-man study and lessons learned

AIMS The aim of the study was to investigate the six-month angiographic and nine-month clinical follow-up outcomes in a first-in-man study using the biodegradable polymer-based cobalt-chromium argatroban-eluting stent (JF-04) for treatment of native coronary atherosclerotic lesions. METHODS AND RESULTS A total of 31 patients with either stable or unstable angina, or silent myocardial ischaemia, exhibiting de novo coronary lesions were enrolled at seven Japanese sites. The lesions were treated with the JF-04 stent after predilatation. The primary endpoint was angiographic in-stent late loss six months after implantation. The secondary endpoints included angiographic restenosis and in-stent volume obstruction by intravascular ultrasound at six months and target vessel failure (TVF) at nine months. Procedural success was achieved in 100% of cases. At six months, angiographic in-stent late loss was 1.01±0.48 mm and binary restenosis was observed in nine cases (29.0%). Among these restenotic cases, most (n=8) demonstrated advanced angiographic restenosis patterns, including diffuse/proliferative restenosis and total occlusion. At nine months, TVF was observed in four cases (12.9%), exclusively attributed to target vessel revascularisation. CONCLUSIONS This argatroban-eluting stent failed to inhibit neointimal hyperplasia sufficiently, despite the theoretical benefits and promising clinical experience with local drug delivery.

Elevated circulating levels of tumor necrosis factor in patients with mitral valve disease and ventricular septum defect.

SummaryElevated levels of circulating tumor necrosis factor (TNF)-α have been reported in patients with decreased left ventricular ejection fraction. Also, TNF has been reported to depress myocardial contractility. In our previous study, no correlation was found between the plasma level of TNF and clinical parameters in patients with cardiomyopathy. In the present study, we detected elevated levels of circulating TNF-α in 5 out of 15 patients with mitral valve disease and in 1 patient with ventricular septal defect whose left ventricular ejection fraction was within the normal range. The levels of TNF-α were not correlated with any hemodynamic parameters. Further studies are necessary to clarify the mechanisms of the regulation and effects of TNF-α in patients with chronic heart failure.

Asymptomatic vascular rings of aorta in adult cardiac surgery patients.

A 70-year-old man presented with recurrent exertional chest oppression. His history included insulin-dependent diabetes, systemic hypertension, hypercholesterolemia, minor stroke, and myocardial infarction with a subsequent percutaneous catheter intervention. Coronary angiography showed severe 3-vessel disease with significant left main stenosis. A double aortic arch was identified incidentally by multidetector computed tomography (Figure 1). Both arches arose from the ascending aorta, gave rise to the common carotid and subclavian arteries, encircled the trachea and esophagus, and joined the descending aorta. The distal ascending aorta and Figure 1. Multidetector computed tomography demonstrating double aortic arch. The aortic arches were balanced and gave rise to the common carotid and subclavian arteries on each side.