Noncanonical Role of Telomerase in Regulation of Microvascular Redox Environment With Implications for Coronary Artery Disease.

Telomerase reverse transcriptase (TERT) (catalytic subunit of telomerase) is linked to the development of coronary artery disease (CAD); however, whether the role of nuclear vs. mitchondrial actions of TERT is involved is not determined. Dominant-negative TERT splice variants contribute to decreased mitochondrial integrity and promote elevated reactive oxygen species production. We hypothesize that a decrease in mitochondrial TERT would increase mtDNA damage, promoting a pro-oxidative redox environment. The goal of this study is to define whether mitochondrial TERT is sufficient to maintain nitric oxide as the underlying mechanism of flow-mediated dilation by preserving mtDNA integrity.Immunoblots and quantitative polymerase chain reaction were used to show elevated levels of splice variants α- and ß-deletion TERT tissue from subjects with and without CAD. Genetic, pharmacological, and molecular tools were used to manipulate TERT localization. Isolated vessel preparations and fluorescence-based quantification of mtH2O2 and NO showed that reduction of TERT in the nucleus increased flow induced NO and decreased mtH2O2 levels, while prevention of mitochondrial import of TERT augmented pathological effects. Further elevated mtDNA damage was observed in tissue from subjects with CAD and initiation of mtDNA repair mechanisms was sufficient to restore NO-mediated dilation in vessels from patients with CAD. The work presented is the first evidence that catalytically active mitochondrial TERT, independent of its nuclear functions, plays a critical physiological role in preserving NO-mediated vasodilation and the balance of mitochondrial to nuclear TERT is fundamentally altered in states of human disease that are driven by increased expression of dominant negative splice variants.

Extension of the measurable temperature range of the LHD Thomson scattering system.

The large helical device Thomson scattering system was designed for the target electron temperature (T(e)) range, T(e) = 50 eV-10 keV. Above 10 keV, the experimental error becomes rapidly worse. In order to obtain reliable T(e) data in the temperature range above 10 keV, we are planning to extend the measurable T(e) range by following two methods. First we have installed one more wavelength channel that observes shorter wavelength region in polychromators. Next applying forward scattering configuration is another candidate. We estimate the data quality when the two methods are used. Both of the two methods are expected to improve T(e) data quality at T(e) ≥ 10 keV.

Improvements of data quality of the LHD Thomson scattering diagnostics in high-temperature plasma experiments.

In Large Helical Device (LHD) experiments, an electron temperature (T(e)) more than 15 keV has been observed by the yttrium-aluminum-garnet (YAG) laser Thomson scattering diagnostic. Since the LHD Thomson scattering system has been optimized for the temperature region, 50 eV≤T(e)≤10 keV, the data quality becomes worse in the higher T(e) region exceeding 10 keV. In order to accurately determine T(e) in the LHD high-T(e) experiments, we tried to increase the laser pulse energy by simultaneously firing three lasers. The technique enables us to decrease the uncertainties in the measured T(e). Another signal accumulation method was also tested. In addition, we estimated the influence of high-energy electrons on T(e) obtained by the LHD Thomson scattering system.

Spin manipulation using the light-shift effect in rubidium atoms.

Optical manipulation of spin coherence in rubidium atoms is studied. The effect of off-resonant and circularly polarized light on optically induced magnetization is investigated. The change in precession frequency caused by the light-shift effect is verified. Absorption-free phase control of spin precession and pure spin rotation about an arbitrary axis are demonstrated. A theory of precession frequency shift that includes the effect of absorption is considered by using the density matrix and the experimental results are in agreement with the predictions of the theory. Thus, we show that it is possible to carry out off-resonant control of spin coherence and all-optical manipulation of spins.

Aortic dissection presenting as concomitant stroke and STEMI.

Aortic dissection is a disease of immediate consequence,as mortality of a proximal dissection is in excess of 50% when left untreated. Early recognition of the dissection event can lead to faster definitive correction with surgical and/or novel percutaneous approaches. Widely varying signs and symptoms can, however, make this diagnosis a challenge, further complicated by the fact that no specific imaging modality is ideal, nor immediately available, in all cases. Care must be taken inpatients where methodical evaluation is difficult,including physical exam, standard electrocardiogram and chest X-ray, before more definitive imaging. This is a case of aortic dissection that is presented as concomitant ST elevation myocardial infarction and embolic stroke, in which the patient received thrombolytics before diagnosis of the dissection itself. This arguably may have worsened her clinical course.

Propagation of femtosecond light pulses in a dye solution: nonadherence to the conventional group velocity.

Propagation of femtosecond light pulses in a resonant absorption medium is studied. The propagation time of the light pulses was measured in a dye solution by the optical-Kerr-gate method. Nonadherence to the conventional group velocity domega/dk , which is defined in weak absorption region, was found. The observed wavelength dependences of the group delay and the spectral change in the anomalous dispersion region are qualitatively in good agreement with the theoretical prediction obtained from the new definitions of group velocity, which can be clearly defined even in strong absorption region.

[Left atrial thrombus in an 80-year-old woman scheduled to have an operation for uterus cancer; report of a case].

An 80-year-old woman was scheduled to have an operation for uterus cancer. Echocardiography revealed a giant mobile mass in the left atrium with a stalk at posterior wall of the left atrium. There was no significant mitral disease. Due to the risks of sudden circulatory collapse and systemic emboli, an emergency operation was indicated. Right side of the left atrium was opened under cardiopulmonary bypass following median sternotomy. The mass was attached to the posterior wall, 1.5 cm medial to the right upper pulmonary vein, with a thin stalk as diagnosed preoperatively. The mass (4.2 x 3.4 x 3.4 cm) was removed very easily. Pathological analysis revealed that the mass was a thrombus mixed with fibrin. A possible cause would be paroxysmal atrial fibrillation and/or hypercoagulative status due to malignancy. Anti-coagulation therapy was initiated postoperatively to prevent recurrence of thrombus. The patient recovered and discharged uneventfully.

UCN Production With a Single Crystal of Ortho-Deuterium.

The present paper reports on the preliminary experimental results concerning a new concept of ultracold neutron production with a single crystal converter of ortho-deuterium lying in the ground rotational state at the low temperature of about 10 K, which should make it possible to utilize a guided cold neutron beam instead of irradiating the converter material in the inside of high radiation fields. The successful observation of the clear Bragg scattering pattern from the single crystal converter and the reasonable results from the first experimental trial of the ultracold neutron production with the single crystal are shown.

Information gain in an optical bistable system by stochastic resonance.

We have shown an experimental demonstration of information gain due to the stochastic resonance in an optical bistable system, that is, information hidden in the input wave form appears in the output of a nonlinear system when the input noise amplitude is adequate. The optical bistable system is a hybrid type comprising a LiNbO3 crystal with an electric feedback loop, and the input of the system is the sum of a binary bit series and a Gaussian colored noise. The information gain is proved to be prominent when the noise cutoff frequency is larger than the bit rate.

Potential use of ultrasound in creating transmyocardial channels.

Although the mechanisms of the clinical benefits of transmyocardial laser revascularization (TMLR) are considered to be angiogenesis with increased perfusion, denervation and placebo effect, it is unknown whether laser energy is a prerequisite in obtaining these beneficial effects. The present study investigated whether it is possible to create transmyocardial channels and induce angiogenesis by ultrasound. Myocardium was penetrated with an ultrasonically activated surgical blade by advancing the blade tip perpendicularly to the left ventricular free wall of the beating heart of 6 mongrel dogs. The power of ultrasound was set at either the lowest or highest of the system. The animals were killed 30 min (acute; n=3) and 2 weeks (chronic; n=3) after channel creation. Holmium:YAG laser, which is currently used for clinical TMLR, was used to create myocardial channels in 4 other dogs, which were also killed 30 min (n=2) and 2 weeks (n=2) after channel creation. The areas of acute channel core, acute thermal damage and chronic fibrosis were compared between the laser and ultrasound channels by Masson's trichrome stain. Factor VIII and proliferating cell nuclear antigen (PCNA) immunostaining were carried out on the samples obtained from chronic animals. The density of vessels and that of proliferating vascular endothelial cells and vascular smooth muscle cells around the channels were measured. The area of acute core was larger in the lowest and highest outputs of ultrasound than in laser channels (0.78+/-0.09, 1.0+/-0.12 vs 0.38+/-0.04 mm2; p<0.01). The area of acute damage in both laser and the highest output of ultrasound channels was greater than in the channels produced by the lowest output of ultrasound (4.43+/-0.28, 4.63+/-0.44 vs 2.90+/-0.29 mm2; p<0.01). The ratio of acute damage area to acute core area was greater in laser channels than in either type of ultrasound channel (16.86+/-1.66 vs 6.04+/-0.67, 7.86+/-1.07; p<0.01) and the area of chronic fibrosis was greater (3.23+/-0.20 vs 1.59+/-0.18, 2.24+/-0.20 mm2; p<0.01). Factor VIII and PCNA immunostaining revealed new vessels not only inside the areas of chronic fibrosis, but also in the surrounding myocardium, in both laser and ultrasound channels. Ultrasound created transmyocardial channels histologically similar to laser channels and angiogenesis was induced in the normal myocardium surrounding ultrasound channels.

Ruptured aortic dissecting aneurysm in Turner's syndrome: a case report and review of literature.

Cardiovascular malformations are frequently observed in Turner's syndrome. Bicuspid aortic valve and coarctation of the aorta are commonly associated with Turner's syndrome whereas aortic dissection is rare but its rupture results in death. We experienced a case of ruptured dissecting aneurysm (Stanford type A) in a 30-year-old female with Turner's syndrome. Emergent total arch replacement was performed successfully. A literature review revealed 32 cases of aortic dissection in patients with Turner's syndrome, including 15 cases of rupture. However, survival after rupture was reported only two cases. To our knowledge, this report descries the third known case of successful surgical management of ruptured aortic dissection in Turner's syndrome.

Coronary artery bypass grafting in the elderly.

BACKGROUND AND METHODS: The incidence of coronary artery bypass grafting (CABG) in elderly patients has been increasing. We retrospectively analyzed the results of CABG performed at Shin-Tokyo Hospital between January 1, 1991, and December 31, 1998. Preoperative, perioperative, and follow-up data of patients > or = 75 years old (group E, n = 190) were collected, and compared with those of patients < 75 years old (group Y, n = 1,380). RESULTS: Female gender, emergent CABG, preoperative balloon pumping use, cardiogenic shock, hypertension, and preoperative cerebral vascular accident were significantly more frequent in group E (p < 0.05). CABG was completed without any significant differences, except for less frequent use of the bilateral internal mammary artery (p < 0.01), more frequent use of the saphenous vein (p < 0.005), and a greater incidence of blood transfusion in group E (p < 0.0001). The postoperative course required longer intubation, ICU stay, and postoperative hospital stay in group E (p < 0.001), and was more frequently associated with major complication (p < 0.0001) and in-hospital death (p < 0.05). During the mean follow-up of 2.7 years (maximum 6.9 years), the actuarial 5-year survival of groups E and Y were 84.3% and 92.5% (p < 0.01), respectively, excluding in-hospital mortality. The actuarial 5-year cardiac event-free rates were 79.9% in group E and 79.7% in group Y, showing no significant difference. CONCLUSIONS: CABG in the elderly carries certain surgical risks. However, the long-term cardiac event-free rate after CABG in the elderly was almost the same as that of younger patients. Inferior long-term survival in the elderly was most likely due to the biological nature of aging.

Histologic evidence that basic fibroblast growth factor enhances the angiogenic effects of transmyocardial laser revascularization.

OBJECTIVES: To determine whether addition of basic fibroblast growth factor (bFGF), an angiogenic growth factor, enhances the angiogenic effects of transmyocardial laser revascularization (TMR). BACKGROUND: TMR is an investigational therapy for treating patients with medically refractory angina not amenable to traditional therapies. Histologic and blood flow studies in animals have suggested that TMR enhances angiogenesis above that normally seen in ischemic myocardium. We tested the hypothesis that bFGF administered into TMR channels further enhance the angiogenic effects of TMR. METHODS: Chronic ischemia was created in 3 groups of dogs using an ameroid constrictor on the proximal LAD. In the bFGF group (n = 5) non-transmyocardial channels were created in the LAD territory and bFGF, (100 ng/ml) dissolved in pluronic gel was injected into the each channel. In the TMR group (n = 7), transmyocardial channels were created without bFGF. A control group (n = 7) had ischemia without TMR of bFGF. 5-bromo-2'-deoxyuridine (BrdU) was administered to mark proliferating cells. After 8 weeks survival, colored microspheres were injected to assess the regional myocardial blood flow. RESULTS: TMR and TMR+bFGF increased total vascular density by approximately 40% over that observed in the control group. However, the number of large vessels (internal diameter > or = 50 microm) was doubled by the addition of bFGF, and this correlated with a 50% increase in the density of proliferating vascular cells and a tripling of the total estimated vascular cross sectional area. Blood flow to the LAD territory was increased by TMR compared to controls, with no further benefit observed in the bFGF group. CONCLUSIONS: On a histologic basis, basic fibroblast growth factor further enhances angiogenesis following TMR in ischemic myocardium mainly by increasing the size but not the total number of vessels.

Factors contributing to pressure overload-induced immediate early gene expression in adult rat hearts in vivo.

We determined the contributions of angiotensin II type 1 receptor (AT(1)) stimulation, adrenergic stimulation, and autonomic activation to pressure overload-induced c-fos expression in the adult rat heart in vivo. c-fos expression was increased in pressure-overloaded hearts created by aortic banding compared with sham-operated rats (458 +/- 100% vs. sham, P < 0.05). GR-138950, a selective AT(1) antagonist, did not blunt this expression (banding vs. banding + GR-138950: 458 +/- 100% vs. 500 +/- 125%, not significant). Atropine and hexamethonium partially decreased c-fos expression (banding vs. banding + atropine/hexamethonium: 700 +/- 67% vs. 400 +/- 67%, P < 0.05). Phentolamine had no significant effect on c-fos expression; however, propranolol inhibited the expression (banding vs. banding + propranolol: 492 +/- 108% vs. 154 +/- 15%, P < 0.05). The inhibition by propranolol was independent of the decreases in heart rate. Thus factors contributing to pressure overload-induced c-fos expression in adult rat hearts in vivo are different from those in neonatal myocytes in vitro undergoing stretch.

Evidence of vascular growth associated with laser treatment of normal canine myocardium.

BACKGROUND: Transmyocardial laser revascularization is a new therapy for patients with refractory angina. Although clinical studies suggest that transmyocardial laser revascularization decreases angina and may improve regional blood flow, the underlying mechanisms are not elucidated. We hypothesized that one mechanism may relate to stimulation of vascular growth in laser-treated regions. METHODS: Transmyocardial laser revascularization channels were made with holmium:yttrium-aluminum garnet or carbon dioxide lasers in eight normal canine hearts; animals were sacrificed 2 to 3 weeks later and examined for vascular density and for evidence of smooth muscle proliferation. RESULTS: The original channels were infiltrated by granulation tissue with associated vascularity. Vascular growth was stimulated immediately surrounding the channel remnant as evidenced by an increase in the number of vessels (approximately twice that of the control region) and an increase in the number of vascular cells staining positive for markers of cellular proliferation. CONCLUSIONS: Transmyocardial laser revascularization leads to local vascular growth as early as 2 weeks after treatment. It remains to be determined whether this mechanism contributes to increased regional blood flow or to clinical benefits associated with this novel form of therapy.

Angiogenesis is enhanced in ischemic canine myocardium by transmyocardial laser revascularization.

OBJECTIVES: This study sought to test whether transmyocardial laser revascularization (TMLR) stimulates angiogenesis in an animal model of chronic ischemia. BACKGROUND: TMLR relieves angina and may also improve blood flow in patients who are not candidates for traditional therapies. The mechanisms of these benefits are not fully defined. METHODS: Ischemia was created in 14 dogs by proximal left anterior descending coronary ameroid constrictors. TMLR was performed in the anterior wall (approximately 1 channel/cm2) of seven dogs; the remaining dogs served as the ischemic control group. Myocardial blood flow was measured (colored microspheres) at rest and during chemical stress (adenosine) in the acute setting and after 2 months. RESULTS: TMLR did not influence blood flow in the acute setting. After 2 months, resting blood flow increased comparably in the anterior wall in both groups to approximately 80% of normal. However, the TMLR-treated dogs demonstrated an approximately 40% increase in blood flow capacity during stress in the ischemic territory compared with untreated dogs (left anterior descending coronary artery/left circumflex coronary artery flow 0.53+/-0.16 in the control group vs. 0.73+/-0.08 in TMLR animals, p < 0.05). Vascular proliferation, assessed by bromodeoxyuridine incorporation and proliferating cell nuclear antigen positivity in endothelial and smooth muscle cells was about four times greater in the TMLR group than in the control group (p < 0.001). The density of vessels with at least one smooth muscle cell layer was approximately 1.4 times greater in the myocardium surrounding the TMLR channel remnants than in control ischemic tissue (p < 0.001). CONCLUSIONS: In this canine model of chronic ischemia, TMLR significantly enhances angiogenesis as evidenced by the increased number of vessels lined with smooth muscle cells, markedly increased vascular proliferation and increased blood flow capacity during stress.

Early Activation of Metalloproteinases after Experimental Myocardial Infarction Occurs in Infarct and Non-infarct Zones.

The collagen matrix of the heart forms a network linking muscle fibers, muscle bundles, and intramyocardial blood vessels. Collagen turnover in the heart is normally a dynamic process that involves both collagen synthesis and degradation. Collagen breakdown generally involves its chemical digestion by matrix metalloproteinases (MMPs) which are activated in tissue repair, wound healing, and myocardial ischemia. We studied activation of MMPs by zymography in infarct (anterolateral wall) and non-infarct (septum) zones of rat hearts following coranary artery ligation, as well as in sham operated rats. Rats were sacrificed at 30 minutes, 1 hour, 2 hours, 4 hours, and 24 hours post infarction (six hearts for each time period). MMP activity was detected at different molecular weights, with bands at 54 kDa (MMP-1), 62 kDa (MMP-2), and 92 kDa (MMP-9) being the most prominent. MMP activities were indexed by densitometer optical reading. Activity was detected as early as 1 hour post infarct in the MI and remote zones at the 54 kDa (MMP-1) ( p < 0.01) and 62 kDa bands (MMP-2) ( p < 0.001), and at 2 hours post infarct in the infarct zone only at 92 kDa (MMP-9) ( p < 0.05). MMPs are activated early after infarction both in the infarct and importantly, non-infarct zones. This may contribute to collagen breakdown, infarct expansion, and left ventricular remodeling, known to occur early after infarction in experimental and clinical settings.

[A successful retraining of the left ventricle with a left ventricular assist device (bio-medicus) after the arterial switch operation].

We experienced the case of a patient with d-TGA, small VSD who underwent arterial switch operation (ASO) at the age of 8 weeks. In pre-operative UCG, the LV posterior wall thickness was only 3.0 mm. LV systolic pressure had dropped to 29 mmHg at the time of operation. After arterial switch and VSD closure, myocardial contractility and coronary perfusion were good without any ST-T changes, however, the patient could not be weaned from cardiopulmonary bypass. Left ventricular assist device (LVAD) was then applied and LV training was performed with appropriate pre and after-load. On the 4th operative day, the patient was successfully weaned from LVAD. Training of the left ventricle with LVAD will be a useful life-saving method in the case of left ventricular failure after arterial switch operation.

Physiology, histology, and 2-week morphology of acute transmyocardial channels made with a CO2 laser.

BACKGROUND: Transmyocardial revascularization with a CO2 laser appears to improve symptoms in patients with refractory angina. However, it remains controversial as to whether blood flow through the channels is the mechanism of benefit, especially in the acute setting. METHODS AND RESULTS: Three protocols were used to test whether blood flows through transmyocardial CO2 laser revascularization channels. First, channels were made in excised, cross-perfused dog hearts (n = 5) using a CO2 laser (The Heart Laser; PLC Systems Inc, Milford, MA; 40 J/pulse) followed by ligation of the proximal left anterior descending coronary artery. Colored microspheres injected into the left ventricular chamber failed to detect any significant transmyocardial blood flow. In the second protocol (n = 4), laser channels were created in the left anterior descending artery territory, the left anterior descending artery was ligated, and the hearts were excised after 24 hours. Triphenyltetrazolium chloride staining revealed that no viable myocardium was detected around the laser channels in the ischemic myocardium. Finally, channels examined 2 weeks after creation in normal (n = 6) or ischemic (n = 4) myocardium did not maintain their original caliber but were invaded by granulation tissue, which included a large amount of smaller vascular spaces and vessels of various sizes. CONCLUSIONS: Transmyocardial laser revascularization channels made with this CO2 laser did not provide acute myocardial perfusion or preserve myocardial viability in the face of acute ischemia. Channel morphology changes dramatically within the first 2 weeks. To the degree that these findings pertain to human myocardium, the results suggest that transmyocardial blood flow may not be the mechanism of benefit of this procedure, particularly in the acute setting.