Involvement of TRAIL/TRAIL-R interaction in IFN-alpha-induced apoptosis of Daudi B lymphoma cells.

Interferon-alpha (IFN-alpha) exerts the anti-tumour effect on various tumours at least partly through induction of apoptosis. Apoptosis is induced by members of the tumour necrosis factor (TNF) family, including Fas (CD95) and TNF-related apoptosis-inducing ligand (TRAIL). In the present study, we examined whether the TRAIL/TRAIL-R system is involved in IFN-alpha-induced apoptosis using Daudi B lymphoma cells. IFN-alpha upregulated the expression of TRAIL within 12 h, as assessed by flow cytometry and RT-PCR, and the level increased with time until 72 h. The levels of both TRAIL-R1 and TRAIL-R2, low in Daudi cells, were enhanced by IFN-alpha. The enhanced TRAIL-R1/-R2 appeared to function as a death-inducing molecule since IFN-alpha-stimulated cells were more susceptible to TRAIL-induced cell death. The IFN-alpha-stimulated Daudi cells or their derived culture supernatants displayed cytotoxicity against TRAIL-sensitive, but not resistant lines. Moreover, the IFN-alpha-induced reduction in mitochondrial membrane potential preceding the induction of apoptosis was substantially prevented by neutralizing anti-TRAIL monoclonal antibody. Taken together, IFN-alpha-induced apoptosis appears to be mediated by the autocrine and/or paracrine loop involving TRAIL/TRAIL-R.

Experimental study of the effects of multi-site sequential ventricular pacing on the prophylaxis of ventricular fibrillation.

Previous studies report a significant prophylactic effect on the occurrence of atrial fibrillation by simultaneous multi-site atrial pacing. We investigated the effects of multi-site sequential ventricular pacing (MSVP), which may be preferable to simultaneous multi-site pacing in terms of the prophylaxis of the occurrence of ventricular fibrillation (VF). Needle electrodes were inserted at ten different epicardial sites on both ventricles for MSVP in 12 adult beagle dogs. Four premature ventricular extrastimuli (PVE) were introduced to provoke VF reproducibly from a separate electrode in the left ventricle. The 4 PVE were applied to try to provoke VF during MSVP in a comparable fashion to the activation sequence during sinus rhythm. We compared the prophylactic effects of MSVP on the inducibility of VF by changing the number of stimulation sites to either 1, 3, 5, or 10 epicardial sites. We performed a total of 363 trials of induction and suppression of VF. The occurrence rates of VF by the 4 PVE for the various number of epicardial stimulation sites of MSVP, i.e., at 1, 3, 5, and 10 sites, were 0.8263, 0.4286, 0.4450, and 0.2857, respectively (p < 0.05). There was a significant prophylactic effect of MSVP on the inducibility of VF, and this effect became stronger as the number of MSVP sites was increased from 3 to 10. The hemodynamic state was relatively stable during MSVP. MSVP seems to be a promising method with which to reduce the occurrence of VF, and a larger number of stimulation sites would be more effective in terms of the prophylaxis of VF.

Detection of silent myocardial ischemia patients by the spatial velocity electrocardiogram.

This study was designed to detect patients with type I silent myocardial ischemia (SMI) at rest by assessing the symmetry of the electrocardiographic (ECG) T wave using the spatial velocity electrocardiogram (SVECG). In this study, the ECG T waves in patients with SMI were symmetric compared with those in normal subjects, and the the c/a ratio in the SVECG-T wave as the index of degree of symmetry of the ECG T wave enabled us to diagnose 73% of these patients; the c/a ratio in the SVECG T wave was a useful index for detecting patients with type I SMI at rest.

Photodynamic therapy of atherosclerosis using YAG-OPO laser and Porfimer sodium, and comparison with using argon-dye laser.

We performed photodynamic therapy (PDT) using the Yttrium Aluminium Garnet-Optical Parametric Oscillated (YAG-OPO) laser in cases of atherosclerosis, and examined its efficacy in vivo. We also performed PDT using an Argon-dye (Ar-dye) laser with the same output, and compared the efficacies. Following balloon denudation injury of the thoracoabdominal aorta, rabbits were raised on a cholesterol diet for 16 weeks, producing atheroma in that region. At 24 h following the administration of Photofrin 5 mg/kg, PDT was performed, and animals were sacrificed at 1 day, 1 week, and 2 weeks following the procedure to examine its efficacy. This was compared with the efficacy of PDT using the Ar-dye laser. Following PDT using a YAG-OPO laser, an increase in the vessel lumen was seen due to reduction of the hypertrophic intima and media, without the appearance of inflammatory cells. This result was seen more strongly in PDT using the pulse wave YAG-OPO laser than with the continuous wave Ar-dye laser, affecting not just the intima but also the media. These data demonstrated that PDT can effectively regress atherosclerotic lesions.

A study to determine if basic fibroblast growth factor (bFGF) reduces myocardial infarct size in acute coronary arterial occlusion.

We investigated the angiogenic and myocardial salvage effects of bFGF. Twelve beagles with ligated left anterior descending coronary arteries were divided into two groups: a FGF group administered bFGF intravenously, and a Control group, after CAG immediately post-ligation. One week post-ligation, CAG was repeated. The heart was sliced along the short axis. For each section, the fluorescein Na staining deficit area (DA) and ratio of DA to total area (DAR), TTC staining of the infarct area (IA) and ratio of IA to total area (IAR), and Masson trichrome staining of the fibrosed area (MA) and ratio of MA to total area (MAR), were calculated. The increase in the number of collateral vessels, seen on CAG from post-ligation to 1 week later, was significantly greater in the FGF group. No significant differences in IAR or MAR were seen between the groups. However, DAR and DA/IA were significantly less in the FGF group. In conclusion, bFGF had no effect on infarct size, but stimulated the growth of collateral vessels and improved coronary blood flow in IA.

[Serial change of TL/BMIPP dual SPECT myocardial scintigram in patients with acute myocardial infarction; meaning of chronic mismatch phenomenon].

This study was aimed to elucidate the serial changes and clinical significance of accumulation mismatch with TL and BMIPP dual SPECT myocardial scintigraphy during 6 months in patients with acute myocardial infarction (AMI). The dual SPECT scintigraphy was performed at one, three and six months after onset of AMI in 46 patients who underwent reperfusion therapy. Long axis fractional shortening in infarct-related area and left ventricular end-diastolic volume index (LVEDVI) were measured by left ventriculography performed immediately after reperfusion and at one, six months after onset of AMI. The patients were divided into two groups: those with mismatch (Group (+)) and those without (Group (-)) at one month after reperfusion. Group (+) was subdivided into three groups according to duration of persistence of mismatch; one month persistence (1 M), three months (3 M) and six months (6 M). Improvement of wall motion abnormality (WMA) in infarct-related area was seen at one month after reperfusion in group 1 M and group 3 M, while group 6 M showed no apparent change in WMA throughout the study period. LVEDI did not change at six months after reperfusion in group 1 M and 3 M, while significant increase was seen in group 6 M. It is concluded that the case with disappearance of mismatch between TL and BMIPP until three months after reperfusion indicates myocardial stunning while in the case with long-standing mismatch left ventricular remodeling is suggested.

[Adult case of isolated noncompaction of left ventricular myocardium revealed at hospitalization for tuberculous pleuritis].

A 48-year-old man was diagnosed with isolated noncompaction of the left ventricular myocardium. He had been suffering from dyspnea during light exercise since early February 1997, which worsened with time. Eventually, he visited our hospital on February 14. He was admitted urgently because orthopnea was observed and chest radiogram showed massive left pleural effusion. The diagnoses were pulmonary tuberculosis and tuberculous pleuritis. Echocardiography at admission showed generalized hypokinesis of the left ventricle, so we suspected that his condition was complicated by myocarditis. However, virus antibody levels were not elevated, and no obvious findings compatible with myocarditis or cardiomyopathy were obtained by right ventricular myocardial biopsy. Left ventricular contractility remained low and a trabecular mesh structure was seen at the left ventricular apex. Thus, the diagnosis was isolated noncompaction of the left ventricular myocardium. This disorder has been highlighted in pediatric patients, but few adult cases have been reported.

[Relation between wall motion and scintigraphic uptake altered by the cut-off level on technetium-99m sestamibi tomographic imaging--the preferable cut-off levels according to tomographic uptake correlated with the wall motion].

BACKGROUND: Whether technetium-99m sestamibi imaging can evaluate myocardial viability is still obscure. It may be partially because the preferable cut-off level for evaluation of the viability is not known. OBJECTIVES: This study was aimed to investigate which cut-off level should be used for estimation of the contractile function, and verify whether technetium-99m sestamibi tomographic imaging can evaluate myocardial viability. METHODS: We studied 45 patients who had had myocardial infarction. They underwent technetium-99m sestamibi imaging, echocardiography, and cardiac catheterization. The myocardial image was divided into 16 segments, each of which was scored according to wall motion on echocardiography with a 4-point scale. The segmental technetium-99m uptake was also scored with a 4-point scale. We investigated the correlation between wall motion and scintigraphic uptake with the use of 7 cut-off levels (from 35% to 65%, in 5% increments). The correlation ranks were compared among patient groups with a number of stenotic vessels. RESULTS: Irrespective of the number of stenotic vessels, the defect score was similarly enlarged according to cut-off levels. The patient groups had the maximum correlation ranks with different cut-off levels, which were 40% for 1-vessel disease (rho = 0.512, n = 160, p = 0.0001), 50% for 2-vessel disease (rho = 0.424, n = 208, p = 0.0001), and 60% for 3-vessel disease (rho = 0.540, n = 272, p = 0.0001). The correlation ranks for all groups were stable, whereas not high, throughout various cut-off levels. CONCLUSIONS: Technetium-99m sestamibi imaging can approximately estimate myocardial viability from the point of view of function, which may be corrected by the careful choice of cut off levels according to the number of the stenotic vessels (40% for 1-vessel disease, 50% for 2-vessel disease, 60% for 3-vessel disease).

Early occurrence of respiratory muscle deoxygenation assessed by near-infrared spectroscopy during leg exercise in patients with chronic heart failure.

The mechanisms of respiratory muscle deoxygenation during incremental leg exercise with expired gas analysis were investigated in 29 patients with chronic heart failure and 21 normal subjects. The deoxygenation and blood volume of the respiratory muscle and exercising leg muscle were assessed by near-infrared spectroscopy (NIRS). To evaluate the influence of the leg exercise on the blood volume of the respiratory muscle, 10 normal subjects also underwent a hyperventilation test with NIRS. The respiratory muscle deoxygenation point (RDP), at which oxygenated hemoglobin starts to decrease, was observed in both groups during exercise. The oxygen consumption (VO2) and the minute ventilation at the RDP in the patients was lower (p<0.01). At the same VO2, the respiratory rate was higher in patients (p<0.01). During exercise, the blood volume of the leg muscle increased, while that of the respiratory muscle decreased. During a hyperventilation test, the minute ventilation was higher than that of the RDP during exercise, the blood volume of the respiratory muscle did not decrease, and the RDP was not detectable. In conclusion, a limited ability to increase perfusion of respiratory muscles during exercise combined with the greater work of breathing results in early respiratory muscle deoxygenation in patients with chronic heart failure.

Effects of nicorandil on aortic input impedance: a comparative study with nitroglycerin.

A study of aortic input impedance was performed to evaluate the effects of nicorandil on the systemic circulation, and the effects were compared with those of nitroglycerin. Sixteen patients with coronary artery disease were divided into 2 age-matched groups. Aortic input impedance was obtained from Fourier analysis of aortic pressure and flow signals at baseline conditions, after intravenous administration of either 4 mg (Group 1) or 8 mg (Group 2) nicorandil, and 20 min after 0.3 mg sublingual nitroglycerin. In Group 1, the first harmonic impedance modulus (Z1, 304+/-140 dyne x s x cm(-5)) and the average of the first to third harmonics (Z1-3, 207+/-99 dyne x s x cm(-5)), indices of wave reflection, significantly decreased (24.4% (p<0.05) and 24.7% (p<0.01), respectively) after nicorandil, and 41.3% (p<0.01) and 33.9% (p<0.01) after nitroglycerin. The effects between the 2 vasodilators were not significantly different. In Group 2, Z1 and Z1-3 (275+/-138 and 196+/-93 dyne x s x cm(-5), respectively) also decreased after administration of nicorandil (28.4% (p<0.01) and 35.9% (p<0.01), respectively), and after administration of nitroglycerin (23.9% (p<0.01) and 28.7% (p<0.01), respectively), without any significant difference between the 2 drugs. Characteristic impedance and total peripheral resistance (R) in both groups remained unchanged except for R after 8 mg nicorandil (from 1830+/-415 to 1433+/-428 dyne x s x cm(-5); p<0.01). Like nitroglycerin, both doses of nicorandil reduced wave reflection. The reduction in R after 8 mg nicorandil is related to decreased tone in the resistance arteries, probably due to potassium channel opener effects.

Elevated circulating levels of basic fibroblast growth factor and vascular endothelial growth factor in patients with acute myocardial infarction.

Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) have both shown strong angiogenetic effects in ischemic animal models and it has been reported that these growth factors were increased after acute myocardial ischemia. However, there have been few reports on the serum levels of bFGF and VEGF after acute myocardial infarction (AMI), in particular there has not been a comparative study of bFGF and VEGF in human subjects. The time course of circulating levels of bFGF and VEGF was examined in 36 patients with AMI who were within 24h of the onset of the AMI. The serum bFGF and VEGF levels of 50 age- and sex-matched healthy volunteers served as the baseline value. All the patients had undergone coronary angiography on the day of admission (Day 0), but prior to that the serum bFGF and VEGF levels were examined by enzyme-linked immunoassay. The serum bFGF and VEGF levels were also evaluated on Days 7, 14 and 28. Creatine kinase, myosin light chain I and troponin-T were measured subsequently and radionuclide examinations were performed during the early phase of AMI to determine the infarct size. The serum bFGF levels were significantly increased at Day 0 and were maintained until Days 7 and 14. Although serum VEGF levels at Day 0 were similar to the baseline values, they showed a remarkable increase by Days 7 and 14. A high serum level of bFGF was detected in the acute phase of AMI, and a later increase in VEGF was determined in the sub-acute phase, which suggest that these 2 growth factors play an important role at different time points of the reconstructing process of infarcted myocardial tissue.

Fluorescence spectrum analysis of atherosclerotic plaque using doxycycline.

Using doxycycline (DOXY), fluorescence spectrum analysis was performed on arteriosclerotic lesions, and the efficacy of this method was examined in basic and clinical studies. In the basic study, DOXY 50 mg was administered intravenously to arteriosclerotic rabbits, and the thoracoabdominal aorta removed. Fluorescence spectral analysis was performed on each specimen, and the fluorescence spectral pattern, peak intensity and degree of intimal hypertrophy were studied. In the clinical study, DOXY 200 mg was administered intravenously to 6 human subjects with stable angina and coronary arterial stenosis of greater than 90%, and coronary angiography, coronary angioscopy and fluorescence spectral analysis were performed. DOXY accumulation in the arteriosclerotic intima of rabbit aortae was confirmed. The fluorescence spectrum was monomodal, peaking at around 532 nm. In the noncalcification group, significant correlation was observed between peak intensity and arteriosclerotic intimal thickness. Using DOXY as a fluorescent marker, it was possible to assess the level of arteriosclerotic intimal hypertrophy. Clinically, it was possible to obtain the DOXY spectrum of the coronary arteries.

Photodynamic therapy for the prevention of intimal hyperplasia in balloon-injured rabbit arteries.

This study was performed to demonstrate accumulation of the photosensitizer hematoporphyrin derivative (HPD) in atherosclerosis and to determine whether intimal hyperplasia, the main cause of restenosis after angioplasty, can be inhibited by photodynamic therapy (PDT). Forty Japanese White rabbits were subjected to balloon endothelial injury in the common iliac artery. Five groups of rabbits, ie, immediately after, or 3, 7, 14 or 28 days after the balloon injury, were injected with HPD. These rabbits were sacrificed 24h after HPD administration, and HPD fluorescence was investigated in the injured arteries by fluorescence microscopy. Other groups of rabbits were injected with HPD 24h before PDT, and they were then subjected to intravascular Hg-Xe flash-lamp irradiation immediately after (0D-PDT), or 3 days (3D-PDT), 7 days (7D-PDT), or 14 days (14D-PDT) after the balloon injury. All rabbits were sacrificed 28 days after the balloon injury, and histological sections of PDT-treated arteries were examined by light microscopy. Slight, uniform HPD accumulation was observed in the injured media immediately after the balloon injury, and throughout the entire media and the neointima on day 7. On day 14, HPD accumulation had diminished in the media and increased in the intima, and on day 28 no HPD remained in the media. In the 0D- or 3D-PDT groups, no inhibition of intimal hyperplasia was observed. In contrast, there was significant inhibition of intimal hyperplasia in the 7D- and 14D-PDT groups, and the most effective inhibition was in the 7D-PDT group. This study demonstrated that PDT with HPD inhibits smooth muscle cell growth and decreases the intimal hyperplasia response in rabbits.

Skeletal muscle deoxygenation during exercise assessed by near-infrared spectroscopy and its relation to expired gas analysis parameters.

The present study was performed to determine the relation between oxygenated hemoglobin (oxy-Hb) changes in working muscles and ventilatory parameters. Six active normal subjects, 21 sedentary normal subjects and 16 patients with heart failure performed an incremental exercise with expired gas analysis. Deoxygenation of the vastus lateralis muscle was monitored for oxy-Hb changes using near-infrared spectroscopy. Near the anaerobic threshold (AT), oxy-Hb started to decrease, forming the first inflection point (P1). Near the respiratory compensation point (RCP), the second inflection point (P2) was observed. Oxygen uptake at the AT, RCP, P1 and P2 decreased in magnitude first in the active normal subjects, then in sedentary normal subjects and finally in the heart failure patients. High correlation was demonstrated between AT and P1 (r=0.8, p<0.0005) and between RCP and P2 (r=0.9, p<0.0005). In 12 sedentary normal subjects who underwent repeat exercise, reproducibility was confirmed for both P1 and P2. Constant work rate exercises were performed in 5 sedentary normal subjects, and in all of them the oxy-Hb remained unchanged below the AT work rate, whereas oxy-Hb decreased above the AT work rate. Exercise capacity, with respect to both working muscle deoxygenation and ventilation, could be evaluated in detail by the concomitant use of near-infrared spectroscopy and expired gas analysis.

The influence of changes in loading patterns on left ventricular relaxation in humans.

This clinical investigation was designed to determine the effect of changes in loading patterns on left ventricular (LV) relaxation when heart rate was maintained constant. Not only were changes noted in total load or time in which load is changed, but also the contour of the ascending aortic systolic pressure wave. Twenty patients were studied. LV and ascending aortic pressure were measured by a multisensor catheter under baseline conditions (C) and after an intravenous injection of 2.5 microg angiotensin (A) and sublingual administration of 0.3 mg nitroglycerin (N). A bipolar pacing catheter was placed in the right atrium to maintain a constant heart rate throughout the protocol. The augmentation index (AI), which characterizes the contour of the ascending aortic systolic pressure wave, was defined as the ratio of the height of the late systolic shoulder/peak to that of the early systolic shoulder/peak in the pulse. The rate of isovolumic LV pressure decline was calculated as a time constant (Tau). Ascending aortic systolic pressures (mmHg) were 127+/-29 (C), 158+/-20 (A) and 109+/-15 (N). AI were 1.61+/-1.14 (C), 2.08+/-1.11 (A) and 1.27+/-1.14 (N). Tau values (msec) were 49+/-4 (C), 54+/-4 (A) and 45+/-5 (N). Tau was prolonged proportionally with increasing AI (p<0.001, r=0.64). It was concluded that late systolic pressure augmentation in the ascending aorta is one important factor that influences the rate of isovolumic left ventricular pressure decline in humans.

Goldenhar syndrome associated with various cardiovascular malformations.

This report presents a 54-year-old woman with Goldenhar syndrome featuring an epibulbar dermoid, left microtia and a left preauricular appendage, and synostosis of the vertebrae. Multiple cardiovascular malformations including Wolff-Parkinson-White syndrome, a partial anomalous pulmonary venous connection, patent ductus arteriosus, an anomalous origin of the coronary arteries, and a right-sided descending aorta were revealed by electrocardiography, echocardiography and cardiac catheterization. Goldenhar syndrome is very rare, but the frequency of cardiovascular malformations in this syndrome is 5-58%. It is necessary to perform a careful evaluation of general malformations, especially cardiovascular malformations.

Experimental study of catheter ablation using ultrasound energy in canine and porcine hearts.

UNLABELLED: We examined the efficacy and safety of ultrasound energy in eliminating the arrhythmogenic substrates of atrial as well as ventricular tissue using a newly developed instrument in both in vivo and in vitro experiments. Ultrasound (US) applicators were tested on 79 lesions created on a beating heart in canine cardiac tissue, and on 64 lesions in porcine heart specimens. US lesions were created by using transducers with frequencies around 5-10 MHz. In the in vivo study, we observed a significant decrease in the amplitude of the electrograms recorded from the tip of the ablation catheter during the US application (p < 0.01). In some sites transmural lesions could be created which were well demarcated. Blood coagulum formation was observed on the tip of the ablation catheter on several occasions. In one dog ventricular fibrillation was provoked by the delivery of ultrasound energy to the left ventricle. In the in vitro study, lesion depth increased significantly with a longer duration of energy delivery when the temperature was maintained table (p < 0.001), and the lesion depth increased significantly with higher temperatures of energy delivery when the duration of US application was maintained (p < 0.05). In both cases, no significant change in surface area was observed. The maximum depth of the lesion was 10.3 mm. CONCLUSIONS: An ultrasound energy system is relatively safe and effective for creating lesions large enough to eliminate arrhythmogenic substrates deep in the ventricular myocardium. Although the US system is free from pop phenomenon, the problem of blood coagulation on the catheter tip remains to be settled.

Assessment of vasoactive agents and vascular aging by the second derivative of photoplethysmogram waveform.

To evaluate the clinical application of the second derivative of the fingertip photoplethysmogram waveform, we performed drug administration studies (study 1) and epidemiological studies (study 2). In study 1, ascending aortic pressure was recorded simultaneously with the fingertip photoplethysmogram and its second derivative in 39 patients with a mean+/-SD age of 54+/-11 years. The augmentation index was defined as the ratio of the height of the late systolic peak to that of the early systolic peak in the pulse. The second derivative consists of an a, b, c, and d wave in systole and an e wave in diastole. Ascending aortic pressure increased after injection of 2.5 microg angiotensin from 126/74 to 160/91 mm Hg and decreased after 0.3 mg sublingual nitroglycerin to 111/73 mm Hg. The d/a, the ratio of the height of the d wave to that of the a wave, decreased after angiotensin from -0.40+/-0.13 to -0.62+/-0.19 and increased after nitroglycerin to -0.25+/-0.12 (P<0.001 and P<0.001, respectively). The negative d/a increased with increases in plethysmographic and ascending aortic augmentation indices (r=0.79, P<0.001, and r=0.80, P<0.001, respectively). The negative d/a reflects the late systolic pressure augmentation in the ascending aorta and may be useful for noninvasive evaluation of the effects of vasoactive agents. In study 2, the second derivative of the plethysmogram waveform was measured in a total of 600 subjects (50 men and 50 women in each decade from the 3rd to the 8th) in our health assessment center. The b/a ratio increased with age, and c/a, d/a, and e/a ratios decreased with age. Thus, the second derivative aging index was defined as b-c-d-e/a. The second derivative wave aging index (y) increased with age (x) (r=0.80, P<0.001, y=0.023x-1.515). The second derivative aging index was higher in 126 subjects with any history of diabetes mellitus, hypertension, hypercholesterolemia, and ischemic heart disease than in age-matched subjects without such a history (-0.06+/-0.36 versus -0.22+/-0.41, P<0.01). Women had a higher aging index than men (P<0.01). The b-c-d-e/a ratio may be useful for evaluation of vascular aging and for screening of arteriosclerotic disease.

[Influence of wall thickness on asynergy during exercise two-dimensional echocardiography in patients with old myocardial infarction].

The relationship between left ventricular wall motion worsening (new asynergy; newly developed or worsened asynergy) in the affected part of old myocardial infarction during exercise two-dimensional echocardiography and the wall thickness at diastole was evaluated in 20 patients with more than 51% diameter stenosis in only the infarcted related artery using symptom-limited graded supine bicycle exercise test and two-dimensional echocardiography. End-diastolic wall thickness at normal part of the wall (WtdN) and infarcted parts (WtdI) on the parasternal short-axis view at the papillary muscle level at rest were measured and the wall thickness ratio, WtdI/WtdN x 100(%), was calculated. The rate pressure product at the time when new asynergy appeared and the appearance time of new asynergy after starting exercise were measured in seconds. Mean values for the 20 patients were wall thickness ratio of 75.7 +/- 10.0% (mean +/- SD), new asynergy appearance time of 219 +/- 116 sec after exercise and rate pressure product of 14,209 +/- 2,997 mmHg. beat/min. Smaller wall thickness ratio was associated with lower rate pressure product levels (r = 0.696, p < 0.01) and shorter appearance time of new asynergy (r = 0.772, p < 0.01). There was no significant correlation between the percentage diameter stenosis of the infarct-related artery and appearance time of new asynergy or rate pressure product. New asynergy appeared at a specific infarcted part of the wall, and thinner walls were associated with shorter appearance time of new asynergy with lower rate pressure product levels, regardless of the severity of stenosis of the infarct-related artery.

Low-dose basic fibroblast growth factor and vascular endothelial growth factor for angiogenesis in canine acute hindlimb insufficiency.

Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) have shown strong angiogenetic effects in ischemic animals; however, whether such a beneficial effect could be achieved using low doses remains to be determined. The effects of identical low-level doses of these substances on the creation of collateral circulation in canine acute hind limb insufficiency were evaluated. Anesthetized dogs that had undergone left femoral artery occlusion received 20 microg (2 microg/kg) intravenous boluses of either bFGF or VEGF 3 times at 2-day intervals for the first week only, animals on vehicle saline injection served as controls. All groups, control (n=8), bFGF-treated (n=8), and VEGF-treated (n=6) underwent angiography, blood flow measurement (in ml/min) on the day of ligation (day 0), and at 7, 14 and 28 days, then underwent ischemic limb muscle biopsy at 28 days. Angiogenic-treated groups showed remarkable enhanced collateral circulation at 7 days, which was maintained up to 28 days, and the main collateral source artery of the angiogenic-treated groups dilated by 14 days. Many neovascularized arterioles in specimens of the angiogenic groups were recognized without any tissue edema or necrosis. Even low doses of bFGF or VEGF were enough to augment collateral circulation with no side-effects, and short treatment after acute ischemia was effective. Low-dose bFGF or VEGF may be therapeutical effective options in patients with acute lower limb vascular disease.