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Background: Although nocturnal Cheyne-Stokes respiration alternating between hyperpnea and hypopnea has been considered a sign of severe heart failure, the clinical status of cardiac patients who exhibit oscillatory ventilation during wakefulness has not been clarified. This study was carried out to determine the relation between oscillatory ventilation during wakefulness and exercise capacity in patients with chronic heart disease. We also evaluated retrospectively whether the presence of oscillatory ventilation influences the long-term prognosis in these patients.Methods: A total of 164 patients with left ventricular dysfunction performed a symptom-limited incremental exercise test. Respiratory gas exchange was measured on a breath-by-breath basis throughout the test. Oscillatory ventilation was defined when clear ventilatory oscillation of at least two consecutive cycles was identified at rest before exercise testing and the difference between the peak and nadir of oscillating ventilation was > 30% of the mean value of ventilation.Results: Oscillatory ventilation was noted in 45 of 164 cardiac patients (27%), and the magnitude (mean +/- SD) of oscillation in these patients was 45.5 +/- 16.9%. Patients with oscillatory ventilation had significantly lower left ventricular ejection fraction than those without it (40.7 +/- 12.7% vs 44.9 +/- 11.6%, p < 0.05). However, parameters of exercise capacity such as the peak oxygen uptake (O(2)), the slope of the increase in O(2) relative to the increase in work rate (DeltaO(2)/DeltaWR), and the ratio of the increase in ventilation to the increase in carbon dioxide output (DeltaE/DeltaCO(2)) were not significantly different between the two groups. The mortality rate during 1,797 +/- 599 days of follow-up did not differ between the groups (p = 0.65).Conclusions: Oscillatory ventilation present at rest before cardiopulmonary exercise testing is not significantly related to the peak O(2), DeltaO(2)/DeltaWR, DeltaE/DeltaCO(2), or prognosis in patients with left ventricular dysfunction. [ABSTRACT FROM AUTHOR]

Background: Although parameters obtained during submaximal exercise are known to be useful for predicting mortality in cardiac patients, it has been a matter of debate whether the submaximal parameters are superior to peak oxygen uptake (VO(2)). For this purpose, we aimed to determine the best index among exercise variables in predicting long-term mortality in patients with chronic heart disease.Methods: The study population consisted of 385 consecutive patients with chronic heart disease who performed a symptom-limited incremental exercise test on a cycle ergometer. Breath-by-breath respiratory gas analysis was used to estimate the peak VO(2), the ratio of the increase in VO(2) to the increase in work rate (WR) [VO(2)/Delta WR], and the ratio of the increase in minute ventilation E to the increase in carbon dioxide output (VCO(2)) [Delta VE/Delta VCO(2)].Results: After 1,899 +/- 495 days of follow-up (mean +/- SD), 33 cardiovascular-related deaths occurred. Nonsurvivors achieved lower peak VO(2), lower VO(2)/Delta VWR, and higher Delta VE/Delta VCO(2) compared to the survivors. In the univariate Cox proportional hazards analysis, peak VO(2), VO(2)/Delta VWR, and Delta VE/Delta VCO(2) were found to be significant prognostic indexes of survival. However, multivariate analysis revealed O(2)/Delta VWR as an independent predictor of mortality and Delta VE/delta VCO(2) as a slightly weaker predictor. In this analysis, the prognostic power of peak O(2) was insignificant.Conclusion: Submaximal respiratory gas indexes are very likely to be more sensitive than peak VO(2) for predicting poor survival in ambulatory patients with chronic heart disease. [ABSTRACT FROM AUTHOR]

Geophysical mass flows, which could endanger our health, lives, and property safety, commonly occur in mountain regions. Although many efforts have been made, transport of granular flows consisting of polydisperse grains, which is influenced by multiple factors, is still not well understood. This work focused on the effect of small spherical grains on the movement of large stones in granular flows of different grain compositions (quartz gravel, glass bead and angular stone), through experimentally measuring mass frequency distributions of granular materials deposited on flat surface. Three characteristic deposition distances (X 20 , X 50 and X 80 ) and one extreme mobility probability (P s ) were extracted from cumulative frequency distributions. It reveals that, in most of cases, the inclusion of glass beads reduced X 20 , X 50 , and X 80 but increased P s for total mass. For angular stone mass, the inclusion of glass beads increased the occurrence frequency of that X 20 , X 50 and X 80 increase, apart from increasing P s . These results indicated small spherical grains could effectively enhance the extreme mobility of large angular stones in mixtures. We hope these results could be helpful for improving our understanding of the transport of geophysical mass flow as well as the grain segregation in different natural environment., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The COVID-19 pandemic across Chinese mainland was gradually stabilized at a low level with sporadic outbreaks, before the emergence of Omicron variant. Apart from non-pharmacological interventions (NPIs), COVID-19 vaccine has also been implemented to prevent and control the pandemic since early 2021. Although many aspects have been focused, the change of the spatiotemporal distribution of COVID-19 epidemic across Chinese mainland responding to the change of prevention and control measures were less concerned. Here, we collected the confirmed case data (including domestic cases and overseas imported cases) across Chinese mainland during both 2020/04-2020/08 and 2021/04-2021/08, and then conducted a preliminary data comparison on the spatiotemporal distribution of confirmed cases during the identical period between the two years. Distribution patterns were evaluated both qualitatively by classification method and quantitatively through employing coefficient of variation. Results revealed significant differences in the homogeneity of spatiotemporal distributions of imported or domestic cases between the two years, indicating that the important effect of the adjustment of prevention and control measures on the epidemic evolution. The findings here enriched our practical experience of COVID-19 prevention and control. And, the collected data here might be helpful for improving or verifying spatiotemporally dynamic models of infectious diseases., (© 2023. The Author(s).)

Purpose: This global phase I trial investigated the safety, efficacy, pharmacokinetics, and pharmacodynamics of lisaftoclax (APG-2575), a novel, orally active, potent selective B-cell lymphoma 2 (BCL-2) inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (R/R CLL/SLL) and other hematologic malignancies (HMs)., Patients and Methods: Maximum tolerated dose (MTD) and recommended phase II dose were evaluated. Outcome measures were safety and tolerability (primary) and pharmacokinetic variables and antitumor effects (secondary). Pharmacodynamics in patient tumor cells were explored., Results: Among 52 patients receiving lisaftoclax, MTD was not reached. Treatment-emergent adverse events (TEAEs) included diarrhea (48.1%), fatigue (34.6%), nausea (30.8%), anemia and thrombocytopenia (28.8% each), neutropenia (26.9%), constipation (25.0%), vomiting (23.1%), headache (21.2%), peripheral edema and hypokalemia (17.3% each), and arthralgia (15.4%). Grade ≥ 3 hematologic TEAEs included neutropenia (21.2%), thrombocytopenia (13.5%), and anemia (9.6%), none resulting in treatment discontinuation. Clinical pharmacokinetic and pharmacodynamic results demonstrated that lisaftoclax had a limited plasma residence and systemic exposure and elicited rapid clearance of malignant cells. With a median treatment of 15 (range, 6-43) cycles, 14 of 22 efficacy-evaluable patients with R/R CLL/SLL experienced partial responses, for an objective response rate of 63.6% and median time to response of 2 (range, 2-8) cycles., Conclusions: Lisaftoclax was well tolerated, with no evidence of tumor lysis syndrome. Dose-limiting toxicity was not reached at the highest dose level. Lisaftoclax has a unique pharmacokinetic profile compatible with a potentially more convenient daily (vs. weekly) dose ramp-up schedule and induced rapid clinical responses in patients with CLL/SLL, warranting continued clinical investigation., (©2023 American Association for Cancer Research.)

Accurate predictions of seed dispersal kernels are crucial for understanding both vegetation communities and landscape dynamics. The influences of many factors, including the physical properties of seeds, the time-averaged wind speed and the wind turbulence, on seed dispersal have been studied. However, the influence of local wind speed reduction around a single shrub element (e.g. a small patch of scrub) on seed dispersal is still not well understood. Here, the spatial distribution of the wind intensity (represented by the wind friction speed u * ) around a single shrub element is described, with an emphasis on the variation in the streamwise direction, and assuming that the time-averaged lateral and vertical speeds are equal to zero. The trajectories of the seeds were numerically simulated using a Lagrangian stochastic model that includes the effects of wind turbulence and particle inertia. The patterns of seed deposition with and without the effect of local wind reduction were compared. The variation in seed deposition with changing wind intensity, release height and shrub porosity were also simulated. The simulation results revealed that the local wind reduction increased seed deposition in nearby regions and therefore decreased seed deposition in the regions farther away. Local wind reduction had a greater impact on short-distance dispersal than on long-distance dispersal. Moreover, the dispersal in the circumferential direction decreased once the motion of a seed moving in the streamwise direction was reduced due to the local wind reduction. As the wind intensity and release height increased, the effect of local wind reduction on seed dispersal weakened. Seed dispersal was both wider and farther as the shrub porosity increased. These results may help explain the disagreement between the mechanistic models and the fitting curves in real cases. In addition, the results of this study may improve the currently used mechanistic models by either increasing their flexibility in case studies or by helping explain the variations in the observed distributions., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Annals of Botany Company.)

Wind speed is one of the most important factors for seed wind dispersal. A wind speed reduction region, which could be influenced by vegetation arrangement, will form in the lee of vegetation and therefore affects the seed dispersal. Here, by taking shrub as an example, quantitative differences in seed dispersals of low vegetation between single element and windbreak-like clumps are numerically investigated. The local variation of stream-wise wind speed is focused. Empirically parameterized functions of leeward wind distributions are employed. It reveals that the accumulative probability of dispersed seeds from a point source with considering leeward wind reduction could be well fitted by a logistic function. For a fixed release height or vegetation porosity, accumulative probabilities for single element and those for windbreak-like clumps would intersect at a leeward location. This intersection location decreases linearly with release height but exponentially with porosity. The fitting parameter r 0 (the center of logistic function) for single element increases as the same manner for windbreak-like clumps, with regard to the increase of release height, porosity, and height. But, the increasing rates for single element are higher than those for windbreak-like clumps. The fitting parameter p (the power index of logistic function) for single element is generally larger than that for windbreak-like clumps. With the increase of release height, p decreases at first but increases then for single element, while it shows opposite trend for windbreak-like clumps. p decreases with porosity for both single element and windbreak-like clumps. But, the decreasing rate for single element is lower than that for windbreak-like clumps. p increases exponentially with height for windbreak-like clumps, while it almost keeps constant for single element. These results suggest the potential importance of vegetation arrangement on seed dispersal and therefore possibly provide additional reason for the disagreement among observed dispersal kernels., Competing Interests: The author declares no conflict of interest., (© 2019 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Air flow around vegetation is crucial for particle transport (e.g., dust grains, seeds and pollens) in atmospheric boundary layer. However, wind acceleration around vegetation is still not well understood. In this work, air flow around a single low solid roughness element (representing a dense shrub patch or clump) in atmospheric boundary layer was numerically investigated, with emphasizing wind acceleration zone located at the two lateral sides. The maximum value of dimensionless horizontal wind speed as well as its location of occurrence and the geometrical morphology and area of wind acceleration zone were systematically studied. It reveals that they could alter significantly with the change of roughness basal shape. The maximum value of dimensionless resultant horizontal speed decreases monotonously with observation height, while the area of wind acceleration zone shows a non-linear response to observation height. The dependence of the maximum speed location on observation height is generally weak, but may vary with roughness basal shape. These findings could well explain the disagreement among previous field observations. We hope that these findings could be helpful to improve our understanding of aeolian transport in sparsely vegetated land in arid and semi-arid region, and wind dispersals of seeds and pollens from shrub vegetation.

Upon interacting with the atmosphere, vegetation could alter the wind distribution and consequently the erodibility of nearby region. The parameterization of wind distribution around vegetation is crucial for the prediction of surface aeolian flux. This paper compared the performances of existing empirical distribution models in the estimation of aeolian flux for shrub vegetation, focusing on distribution pattern and vegetation porosity (main parameter of distribution function). Predicted dust fluxes directly entrained by air flow show weak sensitivity to both distribution pattern and porosity in the case of low vegetation density, which suggests some aspects in dust forecast models might be simplified. However, both distribution pattern and porosity show significant effect on sand saltation transport rate in the lee of vegetation element and, consequently, on the formation and evolution of surface aeolian landforms. The contribution of dust fluxes released in wind increase zone to the total emission by using current parameterizations increases with both the decrease of wind speed and the increase of vegetation density. Nevertheless, the parameterization of wind increase zone needs to be validated and improved by further experimental and numerical investigations.

Many cervical cancer (CC) patients suffer from cancer invasion and lymph node metastasis, resulting in poor therapeutic outcome. Evidence has indicated the involvement of misexpressed high-mobility group AT-hook 2 (HMGA2) in poor survival of cancer patients. This study hereby aims to investigate the role of HMGA2 in CC cell biological functions via the ATR/Chk1 signaling pathway. The cell line with the highest HMGA2 expression was selected to establish cell lines with wild-type and stable HMGA2 silencing. The underlying regulatory mechanisms of HMGA2 in CC cells were analyzed with the treatment of the ATR/Chk1 signaling pathway activator, inhibitor, shRNA against HMGA2 or pcDNA-HMGA2 plasmids, followed by quantification of expression levels of ATR, Chk1, Bcl-2, Bax, MMP-2, MMP-9, E-cadherin and N-cadherin. CC cell apoptosis, proliferation, migration, invasion and lymph node metastasis in nude mice were evaluated. The HeLa cell line with the highest HMGA2 expression was selected. HMGA2 inhibited the activation of the ATR/Chk1 signaling pathway. Notably, HMGA2 silencing or inhibition of the ATR/Chk1 signaling pathway inhibited epithelial mesenchymal transition (EMT), CC cell proliferation, invasion, migration, tumorigenicity and lymph node metastasis while promoting apoptosis, indicated by reduced expression of Bcl-2, MMP-2, MMP-9 and N-cadherin, with increased expression of E-cadherin and Bax. Collectively, our study provides evidence that HMGA2 gene silencing inhibits the activation of the ATR/Chk1 signaling pathway, whereby repressing EMT, proliferation, migration and invasion of CC cells and lymph node metastasis, and promoting CC cell apoptosis., Competing Interests: None.

The present study aimed to investigate the protective effects of magnolol on acute 2,4,6-trinitrobenzene sulfonic acid (TNBS)‑induced colitis, and its underlying mechanisms. Experimental colitis was induced by intracolonic administration of TNBS/ethanol into rats. The model rats were randomly assigned into groups: TNBS, magnolol (high, medium and low doses), and salazosulfapyridine (positive control). All intervention regimens were administered by oral gavage, once a day for 7 consecutive days, 24 h after colitis induction. Histological and biochemical changes in colonic inflammation were evaluated by hematoxylin and eosin and immunohistochemistry, respectively. Rats treated with all doses of magnolol exhibited decreased colonic myeloperoxidase activity (P<0.05 vs. TNBS), reduced serum levels of proinflammatory cytokines [including interleukin (IL)‑6 and IL‑17], and downregulated Toll‑like receptor-4 (TLR‑4) mRNA expression. Histological analysis revealed that medium and high doses of magnolol conferred an anti‑inflammatory effect, which was indicated by a decrease in disease activity index, an increase in thymus index, and downregulation of nuclear factor (NF)‑κB p65 mRNA and TLR‑4 protein expression. However, only high‑dose magnolol significantly ameliorated the elevated colon weight/length ratio. The results of the present study indicate that magnolol exerts protective effects against acute TNBS‑induced colitis in rats, and the TLR‑4/NF‑κB signaling pathway‑mediated inhibitory effect on inflammatory cascades may contribute to the protective activity of magnolol.

Background: Atrial fibrosis is a hallmark of atrial structural remodeling leading to the persistence of atrial fibrillation. Although fibroblasts play a major role in atrial fibrosis, their source in the adult atrium is unclear. We tested the hypothesis that endothelial cells contribute to fibroblast accumulation through an endothelial-mesenchymal transition in the atrium of patients with atrial fibrillation., Methods and Results: The study group consisted of patients with atrial fibrillation and valvular disease or atrial septal defect who underwent left atrial appendectomy during cardiac surgery (n=38). The amount of fibrotic depositions in the left atrium positively correlated with left atrial dimension. Furthermore, snail and S100A4, indicative of endothelial-mesenchymal transition, were quantified in the left atrium using western blot analysis, which showed statistically significant correlations with left atrial dimension. Immunofluorescence assay of the left atrial tissue identified snail and S100A4 being expressed within the endocardium which is composed of CD31 + cells. The snail-positive endocardium also showed the expression of membrane type 1-matrix metalloproteinase. Immunofluorescence multi-labeling experiments identified that heat shock protein 47, prolyl-4-hydroxylase, and procollagen type 1 co-localized with snail and S100A4 within the endothelial cells of the left atrium, indicating the mesenchymal phenotype to produce collagen., Conclusions: In this study, we showed that the endothelial-mesenchymal transition occurs in the atrium of patients with atrial fibrillation. This observation should help in constructing a novel therapeutic approach for preventing atrial structural remodeling., (Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Gold nanoparticles have proven to be promising for decentralized nucleic acid testing by virtue of their simple visual readout and absorbance-based quantification. A major challenge toward their practical application is to achieve ultrasensitive detection without compromising simplicity. The conventional strategy of thermocycling amplification is unfavorable (because of both instrumentation and preparation of thermostable oligonucleotide-modified gold nanoparticle probes). Herein, on the basis of a previously unreported co-precipitation phenomenon between thiolated poly(ethylene glycol)/11-mercaptoundecanoic acid co-modified gold nanoparticles and magnesium pyrophosphate crystals (an isothermal DNA amplification reaction byproduct), a new ultrasensitive and simple DNA assay platform is developed. The binding mechanism underlying the co-precipitation phenomenon is found to be caused by the complexation of carboxyl and pyrophosphate with free magnesium ions. Remarkably, poly(ethylene glycol) does not hinder the binding and effectively stabilizes gold nanoparticles against magnesium ion-induced aggregation (without pyrophosphate). In fact, a similar phenomenon is observed in other poly(ethylene glycol)- and carboxyl-containing nanomaterials. When the gold nanoparticle probe is incorporated into a loop-mediated isothermal amplification reaction, it remains as a red dispersion for a negative sample (in the absence of a target DNA sequence) but appears as a red precipitate for a positive sample (in the presence of a target). This results in a first-of-its-kind gold nanoparticle-based DNA assay platform with isothermal amplification and real-time monitoring capabilities.

Incident angle of saltating particles plays a very important role in aeolian events. In this paper, the incident angles of sand particles near the sand bed were measured in wind tunnel. It reveals that the incident angles range widely from 0° to 180° and thereby the means of angles are larger than published data. Surprisingly, it is found the proportion that angles of 5°-15° occupy is far below previous reports. The measuring height is probably the most important reason for the measurement differences between this study and previous investigations.

Water-in-oil submicron emulsions were used as carrier for the topical delivery of 5-fluorouracil (5FU). The effect of components such as level and hydrophilic-lipophilic balance (HLB) value of surfactant, type of cosurfactant, and drug concentration on the delivery capability of drug in the receptor fluid and in the various skin layers (stratum corneum, epidermis and dermis) were evaluated. The result showed the submicron emulsion could increase the transdermal and deposition of 5FU compared with the aqueous control. Submicron emulsion with surfactant at HLB of 6.0 had higher deposition amount of drug in epidermis layer. The deposition amount of drug in the skin layers increased with increased amounts of surfactant and drug loading of submicron emulsion. However, the 0.2% 5FU-load submicron emulsion showed a comparable deposition effect in various skin layers with the commercial product (5%, Efudix®), which indicated that the submicron emulsions could be a promising drug vehicle for topical application.

Objectives: This study aimed to test the hypothesis that the range of 24-h total heart beats (24 h-tHB) correlates with cardiac outcomes (cardiac death and incidence of hospitalization with heart failure) in patients with permanent atrial fibrillation (AF)., Methods and Results: We divided 252 consecutive outpatients with permanent AF into 4 groups according to their 24 h-tHB and examined clinical outcomes. Initial 24 h-tHB at enrollment was significantly associated with patient characteristics including age, sex, presence of structural heart diseases, and left ventricular ejection fraction (EF). The cumulative incidence of heart failure was high in the lowest 24 h-tHB group compared with other groups and significantly different from the highest one (23.9% vs. 7.2% at 5 years, p=0.0074). Multivariate analysis showed that 24 h-tHB<100,000 was associated with cardiac events [hazard ratio, 2.45; 95% confidence interval (CI), 1.09-5.49; p=0.03), along with structural heart disease (hazard ratio, 9.81; 95% CI, 3.34-28.83; p=0.0001) and EF (hazard ratio, 0.97; 95% CI, 0.94-0.99; p=0.002)., Conclusions: Surprisingly, low but not high heart rate was significantly associated with higher incidence of heart failure in Japanese patients. This finding should be further evaluated in future prospective studies., (Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

In this study, submicron emulsions have been employed as a carrier for the topical application of kaempferol. The effect of components of submicron emulsions on the physicochemical properties and permeation capability of drug were evaluated. In case of drug-loaded submicron emulsions, the cumulative amount over 12 h (Q(12 h)), lag time and deposition in skin amount ranged from 13.0±3.4 to 236.1±21.2 µg/cm(2), 1.7 to 5.3 h, and 1.10 to 7.76 µg/cm(2), respectively, which indicated that the permeation parameters of kaempferol were markedly influenced by the component ratio. Kaempferol dispensed in isopropyl myristate was used as the control. The Q(12 h), lag time and deposition amount in skin were 4.2±1.8 µg/cm(2), 6.0 h and 2.25±0.60 µg/cm(2), respectively. The data showed that used appropriate submicron emulsions as vehicle could significantly increase the Q(12 h) and deposition amount in skin and shorten the lag time, demonstrating that submicron emulsions have a potent enhancement effect for kaempferol transdermal delivery.

The aim of the current study was to find an optimal estradiol-loaded microemulsion with higher permeation rate and shortened lag time (LT) for transdermal application by using a response surface methodology (RSM) and constrained mixture design. Isopropyl myristate (X1 ), distilled water (X2 ), and ethanol (X3 ) were selected as independent variables, whereas the viscosity of microemulsion and permeation parameters including the cumulative amount at 24 h (Q24h ) and LT of estradiol-loaded microemulsion through skin were set as dependent variables. The result showed that the three independent variables had a remarkable effect (p < 0.05) on the dependent variables. Moreover, the predicted and observed values of these three dependent variables of the optimal microemulsion formulations, which were produced by the RSM optimization technique, were close, demonstrating that RSM was a useful technique for optimizing pharmaceutical formulations. However, the experimental estradiol-loaded microemulsion with higher permeation rate was expected to provide effective therapeutic concentration in a workable administration area., (Copyright © 2011 Wiley-Liss, Inc.)

Background: Diabetes mellitus promotes atrial structural remodeling, thereby producing atrial arrhythmogenicity, where advanced glycation endproducts (AGEs) and their receptor (RAGE) are implicated to play a role in the pathogenesis., Purpose: We investigated the effects of candesartan, an angiotensin type II receptor blocker, on the diabetes-induced atrial structural change., Methods and Results: Diabetes was induced in 8-week-old female Sprague-Dawley rats by intraperitoneal injection of streptozotocin at 70 mg/kg. Osmotic pumps were simultaneously set to infuse candesartan at a subdepressor dose of 0.05 mg/kg/day. Twelve weeks after the induction of diabetes, the blood glucose and glycated hemoglobin A1c were significantly higher in streptozotocin-injected rats than those in control rats, and were not affected by candesartan treatment. The atria of diabetic rats showed remarkable diffuse interstitial fibrosis with more enhanced protein expressions of RAGE and connective tissue growth factor (CTGF) compared with control ones. The treatment with candesartan significantly reduced CTGF expression and effectively suppressed the development of fibrotic deposition in diabetic animals., Conclusions: Candesartan reduced CTGF expression and attenuated the fibrosis in diabetic rat atria. These results implied the protective effects of candesartan on diabetes-related atrial arrhythmias., (Copyright © 2011 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Objective: To analyze possible difference in bronchial asthma between ethnic and geographic groups and explore its correlates among Uygur and Han adults in Turpan Prefecture, Xinjiang., Methods: One hundred and sixty-six clinically diagnosed asthmatic patients at Turpan Prefecture Hospital, Xinjiang, 86 of Uygur and 80 of Han ethnic, and 166 1:1 matched controls from ophthalmological outpatient department at the same hospital were recruited into the study. Interview with questionnaire was conducted and serum levels of eosinophilic cation protein (S-ECP), total IgE (T-IgE) and specific IgE (S-IgE) were measured for all of the participants to study related factors for asthma with univariate and multivariate conditional logistic regression analyses., Results: Bronchial infection (OR(U) = 5.111, 95%CI: 1.203 - 21.710; OR(H) = 2.498, 95%CI: 1.471 - 5.069), family history of asthma (OR(U) = 3.078, 95%CI: 1.812 - 5.188; OR(H) = 2.711, 95%CI: 1.010 - 6.176), personal allergy history (OR(U) = 2.083, 95%CI: 1.043 - 4.162; OR(H) = 3.998, 95%CI: 1.739 - 9.198), weather change (OR(U) = 2.218, 95%CI: 1.199 - 3.778; OR(H) = 1.733, 95%CI: 1.004 - 2.994) and positive S-IgE (OR(U) = 1.592, 95%CI: 1.018 - 2.491; OR(H) = 3.858, 95%CI: 2.246 - 8.507) correlated with asthma in patients of both Uygur and Han ethnic. Percentage of asthma attack induced by respiratory infection [59.30% (51/86)] and weather change [36.05% (31/86)] in Uygur patients was significantly higher than that in Han ethnic [42.50% (34/80) and 21.25% (17/80), respectively], but percentage of those with personal allergy history [48.75% (39/80)] and positive S-IgE [52.50% (42/80)] in Han ethnic was significantly higher than that in Uygur [32.56% (28/86) and 30.23% (26/86), respectively]. Levels of S-ECP and T-IgE in patients with moderate and severe asthma of both Uygur and Han ethnic [(S-ECP(U) = 7.95 +/- 3.98) microg/L, S-ECP(H) = (11.21 +/- 4.74) microg/L, T- IgE(U) = (72.23 +/- 45.92) kU/L, T-IgE(H) = (108.81 +/- 64.07) kU/L, respectively]were significantly higher than those in controls of the same ethnic [S- ECP(U) = (1.94 +/- 1.16) microg/L, S-ECP(H) = (2.07 +/- 1.63) microg/L, T-IgE(U) = (46.19 +/- 32.47) kU/L, T-IgE(H) = (50.97 +/- 38.51) kU/L; t values were 8.96, 10.52, 2.81, 4.97, P < 0.01], higher in Han ethnic than those in Uygur (t values were 3.01, 2.68, P < 0.01)., Conclusion: Bronchial infection, family asthma history, personal allergy history, weather change and positive S-IgE all were important correlates of asthma in Turpan Prefecture, Xinjiang. Levels of S-ECP and T-IgE in patients with moderate and severe asthma increased during its attacks, higher in Han ethnic than those in Uygur. Genetic and environmental factors may be involved in occurrence and development of asthma.

Background: Since the prevalence of atrial fibrillation (AF) increases progressively with aging, especially in men, we hypothesized that testosterone might affect the occurrence of AF., Methods and Results: We examined the electrophysiological properties of the atria in isolated-perfused hearts of sham-operated male (SM), female (SF), orchiectomized male with and without administration of testosterone (ORCH-T and ORCH), and ovariectomized female (OVX) Sprague-Dawley rats. An electrophysiological study revealed that repetitive atrial responses induced by electrical stimuli significantly increased in ORCH rats without changes in other electrophysiological properties and were abolished by administration of testosterone. To investigate the underlying mechanisms, we evaluated the expression level of calcium-handling proteins. In ORCH rats, the immunoreactive protein level of ryanodine receptor type 2 (RyR2) and sodium-calcium exchanger significantly increased as compared with SM and ORCH-T rats without alterations in the level of FK506-binding protein (FKBP12.6), sarcoendoplasmic reticulum Ca-ATPase, and phospholamban. Immunoprecipitation analysis demonstrated decreased binding of FKBP12.6 to RyR2 in ORCH rats, which was prevented by testosterone. In contrast, the expression levels of these proteins showed no significant differences between SF and OVX rats., Conclusion: Deficiency of testosterone was arrhythmogenic in rat atria possibly through less binding of FKBP12.6 to RyR2, which could induce feasible calcium leakage from the sarcoendoplasmic reticulum. These results would explain, at least in part, the increase in the prevalence of AF in accordance with the decline of testosterone particularly in elderly men.

Background: It is well-known that both B-type natriuretic peptide (BNP) and peak oxygen uptake (VO(2)) are independent predictors of mortality in patients with heart failure. This study investigates the predictive power of BNP and peak VO(2) for survival in cardiac patients., Methods and Results: A total of 609 patients with cardiac disease participated in the study. They underwent cardiopulmonary exercise testing to determine peak VO(2), with BNP being measured before exercise testing During 502.5 median follow-up days, 29 patients died of cardiovascular disease. In the univariate Cox proportional hazards analysis, peak VO(2) and BNP were both found to be significant prognostic indices for survival. The time-dependent ROC curve analysis (Heagerty 2006) was applied to 3 predictors: peak VO(2), BNP, and then both, with gender and age as adjusted variables. The area under the curve (AUC) compared with the follow-up period curves of peak VO(2) and the 2 combined variables (ie, BNP and peak VO(2)) were consistently over that of BNP. The integrated AUC indices were 0.80 (peak VO(2)), 0.81 (peak VO(2) and BNP) and 0.70 (BNP), respectively., Conclusions: These results indicate that peak VO(2) is more potent than BNP for predicting the mortality in patients with mixed cardiac disease.

Background: Diabetes mellitus (DM) is one of the independent risk factors for atrial fibrillation (AF). Our previous study has indicated that DM causes atrial structural remodeling with intraatrial conduction disturbances. We tested the hypothesis that the advanced glycation end products (AGEs) and the receptor for AGE (RAGE), which have been implicated in diabetic complications, are responsible for the atrial structural remodeling., Methods and Results: Diabetes was induced by streptozotocin (65 mg/kg i.p.) in 8-week-old female Sprague-Dawley rats. When 24 weeks old, their atria were subjected to histology, Western blotting, and immunohistochemistry. The HbA(1c) value of induced-DM rats was significantly higher than that of control rats. Histological and immunohistochemical examinations revealed that the atria of diabetic rats showed remarkable structural changes characterized by diffuse interstitial fibrosis with abundant expressions of RAGE and connective tissue growth factor (CTGF), which findings were also confirmed by Western blotting analysis. This diabetes-induced atrial fibrosis was remarkably prevented by administration of an inhibitor of AGEs formation, OPB-9195, along with reduction of CTGF expression., Conclusions: DM promoted atrial structural remodeling via the activation of the AGEs-RAGE system with upregulating CTGF. The inhibition of AGEs formation could be a novel upstream therapeutic approach for diabetes-related atrial fibrosis.

Background: During anticoagulation for prevention of stroke in patients with non-valvular atrial fibrillation (NVAF), bleeding is the most serious complication. In Western countries, the incidences of major bleeding and intracranial hemorrhages with low-dose warfarin are known to occur at a rate of 0.4-1.3% and 0.2% per year, respectively. The purpose of this study was to investigate the incidence and risk factors for major bleeding related with warfarin therapy in Japanese patients with NVAF., Methods and Results: From August 2004 to July 2005, 667 NVAF patients treated with warfarin for NVAF were followed-up. The target prothrombin time-international normalized ratio (PT-INR) value was set at 1.6-2.6 (low-dose warfarin). The exposure on warfarin was 503 patient-years (average PT-INR 2.00 +/-0.40). During the follow-up period, 12 major bleeding complications occurred (2.38% per patient-year), which included 3 intracranial hemorrhages (0.60% per patient-year). Among the patients' characteristics, average PT-INR > or =2.27 during the study was identified as an independent risk factor for major bleeding., Conclusions: The incidence of major bleeding and intracranial hemorrhages in Japanese NVAF patients with low-dose warfarin therapy was 2.38% and 0.60% per patient-year, respectively, which is higher than in Westerners.

Aims: Various pathological conditions can alter cardiac electrophysiological properties not only by physiological responses but also by modifying the gene expression of ion channels (electrical remodelling). To investigate the underlying mechanisms of the latter, electrophysiological alterations would require a simultaneous and comprehensive analysis of the mRNA level of the ion channel genes., Methods and Results: We designed 19 cardiac ion channel cDNA templates to analyse the corresponding mRNAs and classified them into three template sets. Those sets were a voltage-dependent K(+) channel series (rat erg, KvLQT1, Kv4.3, Kv4.2, Kv2.1, Kv1.5, Kv1.4, Kv1.2), an inwardly rectifying K(+) channel series (rat Kir6.2, SUR2A/B, Kir3.4, Kir3.1, Kir2.2, Kir2.1), and an inward cationic ion channel series (rat SCN5A, alpha1C, beta2, alpha2delta2 of cardiac L-type Ca(2+) channel and alpha1G). These cDNA templates were used to synthesize antisense digoxigenin-labelled RNA probes. An amount of the total RNA of 25 microg was adequate to analyse simultaneously the mRNA levels of the ion channel genes with the use of multi-probe RPA, and these three multi-probe template sets enabled us to evaluate the profile of the spatial and temporal transcripts of the cardiac ion channels., Conclusion: The newly developed ion channel multi-probe RPA templates provide an aid in the comprehensive analysis of the electrical remodelling of the heart.

Introduction: Diabetes mellitus is one of the significant independent risk factors for the development of atrial fibrillation (AF). However, the pathophysiological mechanisms of the relationship have not been fully elucidated., Methods and Results: The genetic type II diabetes (GK) rats and their original (Wistar) ones were subjected to electrophysiological (n = 8 per group) and histological (n = 7 per group) studies. At 40 weeks old, when GK rats had significantly (P < 0.01) more increased plasma glucose and HbA(1c) values than Wistar rats, atrial electrical stimuli in the isolated-perfused hearts induced significantly greater number of repetitive atrial responses in GK rats than in Wistar rats (47.9 +/- 17.5 vs 3.1 +/- 1.3 beats, respectively, P < 0.01). GK rats showed significantly longer intra-atrial activation time than Wistar rats (18.3 +/- 0.4 ms vs 15.9 +/- 0.5 ms, P < 0.01) without any significant difference in the atrial refractoriness. The histological examination revealed significantly increased diffuse fibrotic deposition in GK rats atria compared with Wistar ones (P < 0.01)., Conclusion: The present diabetic GK rat showed increased atrial arrhythmogenicity with intra-atrial conduction disturbance, and thus indicated that the structural remodeling of atrium characterized by diffuse interstitial fibrosis would be a major substrate for diabetes-related AF.

Background: Many pathological conditions induce electrical remodeling, possibly through intracellular Ca2+ overload, but the currently available L-type Ca2+ channel blockers may be detrimental because of their global negative inotropic effects., Methods and Results: To determine whether the L-type Ca2+ channel is identical throughout the heart, the distribution of the mRNAs and proteins comprising the L-type Ca2+ channel and its electrophysiological properties were analyzed in rat atria and ventricles. The mRNA of alpha2delta-2 (Cacna2d2) was more abundantly expressed in the atrium (approximately 5-fold) than in the ventricle. In contrast, alpha1C (Cacna1c) (Cav1.2) mRNA was significantly less abundant in the atrium. The level of the alpha1C (Cacna1c) (Cav1.2) protein was decreased (approximately 0.5-fold) and that of alpha2 delta-1 (Cacna2d1) was increased (approximately 2-fold) in the atrium compared with the ventricle. Although the peak ICa,L density showed no significant differences, voltage dependence of inactivation and activation of the current showed a more depolarized shift in the atrium than in the ventricle., Conclusion: These results indicate that in the rat heart the L-type Ca2+ channel differs between the atrium and ventricle with regard to gene expression and electrophysiological properties.

Background: The goal of the present study was to test if ambulatory Holter recordings can predict the electrophysiologic study (EPS) findings in patients with supraventricular tachycardia (SVT)., Methods and Results: The study involved 110 patients with SVT who underwent Holter recording, and then EPS. The hypotheses were that (1) a P'R interval of premature atrial complexes (PACs) between 280 and 400 ms in the Holter recordings predicted dual atrioventricular nodal (AVN) pathways, (2) P'R interval >400 ms predicted triple or more AVN pathways, and (3) SVT initiated by a single PAC suggested easy SVT induction during the EPS. The EPS revealed dual AVN pathways in 14 (93%) of 15 patients with P'R intervals between 280 and 400 ms on the Holter recordings, and triple or more AVN pathways in 18 (90%) of 20 patients with P'R intervals >400 ms. In addition, a single extrastimulus easily induced SVT during the EPS in 11 (85%) of 13 patients in whom SVT was initiated by a single PAC during Holter recording., Conclusion: The ambulatory Holter recording criteria specifically predicted the EPS findings, thereby providing useful advance information.

A 65-year-old man with Brugada-type electrocardiogram (ECG) was admitted to our hospital for chest pain, palpitation and faintness. In the cardiac electrophysiological study, no ventricular tachyarrthymia was induced either at baseline or after pilsicainide (50 mg) infusion. Intravenous administration of pilsicainide exaggerated ST-segment elevation in V(1-4) and converted it to the coved type in V(1), accompanied by severe chest pain. Coronary angiography revealed the vasospasm of the right coronary artery was induced by pilsicainide, not by ergonovine. This is the first case report of coronary vasospasm induced by a pure sodium channel blocker in a patient with Brugada-type ECG.

Background: The magnitudes of the first (WI1) and the second wave-intensity peak (WI2) during the ejection period can be used as indices of left ventricular (LV) contractility and relaxation, respectively. However, use of WI to characterize LV dp/dt and the end-diastolic volume (V ed) relationship may be more problematic, as WI may be affected by changes in preload., Methods and Results: The LV pressure-volume data sets, consisting of 23 recordings obtained by the conductance method from 12 heart disease patients, were studied. End-systolic elastance (E es) and volume-axis-intercept (V0) were calculated with varying preload. Time constant of LV relaxation (tau), V ed, and WI were calculated from steady-state averaged data. The E es showed a weak correlation with WI1 (r = 0.46, p < 0.05) but a better correlation with preload-adjusted WI1 [WI1/V ed; r=0.86, WI1/V(ed)2; r = 0.92, WI1/(V ed - V0)2; r = 0.89, all p < 0.01]. Similarly, tau did not correlate with WI2 but did correlate with preload-adjusted WI2 [WI2/V ed; r = -0.73, WI2/V(ed) 2; r = -0.63, WI2/(V ed - V0)2; r = -0.78, all p < 0.01]., Conclusions: These data demonstrate the importance of preload-adjustment when using the WI index for simultaneous assessment of LV contractility and relaxation.

Antiarrhythmic drugs exert their effects by inhibiting the ion channels of cardiomyocytes. However, these effects could also modify the ionic environment around them, and thereby affect the expression of ion channels, leading to biochemical enhancement or attenuation of the antiarrhythmic effects. To test this hypothesis, the physiological and biochemical effects of cibenzoline were evaluated in a rapid atrial pacing model in rats. In rats with rapid atrial pacing, pretreatment with cibenzoline significantly inhibited the increases in Kv1.5 mRNA at 2 hours and immunoreactive protein at 4 hours by 35 +/- 15% and 30 +/- 10%, respectively. These effects were observed only in the rapid atrial pacing group, not in the sham-operated group. With cibenzoline pretreatment, 4-hour rapid atrial pacing resulted in significant prolongation of the atrial refractory period compared to the untreated group even after removal of cibenzoline. In contrast, the sham and rapid atrial pacing model with and without cibenzoline pretreatment showed similar acute physiological responses to cibenzoline. In conclusion, in addition to the acute physiological effects, pretreatment with cibenzoline exerted pleiotropic effects of inhibition of Kv1.5 channel upregulation by rapid pacing, implying differences in the cibenzoline effects when administered before and after onset of paroxysmal atrial fibrillation.

Evaluating blood pressure response during exercise rather than during rest might better detect a subtle impairment in relaxation of the resistance vessel in hypercholesterolemia. We examined the relation between serum cholesterol and blood pressure response during exercise in patients with coronary artery disease. One hundred and forty-eight consecutive patients with coronary artery disease were monitored during symptom-limited incremental exercise testing with a cycle ergometer. Cuff blood pressure was measured every minute during exercise testing with an automatic indirect manometer. Although there were no significant differences in systolic or diastolic blood pressure at rest between the patients with hypercholesterolemia (total cholesterol > or = 220 mg/dL, n = 39) and those without it (n = 109), the former reached a higher diastolic blood pressure at peak exercise (94.8+/-16.0 versus 87.8+/-12.9 mmHg, P = 0.007). The increase in diastolic blood pressure at peak exercise versus the resting value in the patients with hypercholesterolemia was 20.6+/-11.3 mmHg, and this was significantly higher than the increase in patients without hypercholesterolemia (14.8+/-11.8 mmHg, P = 0.009). However, there were no differences in the peak exercise systolic blood pressure and the magnitude of the increase in systolic blood pressure between the two groups. Among the patients with coronary artery disease in our study, we found that those with hypercholesterolemia had significantly higher diastolic blood pressure during exercise than those without hypercholesterolemia, strongly suggesting that patients with hyperlipidemia are at a higher risk of developing hypertensive complications.

We compared cerebral oxygenation during exercise and during exercise recovery between 22 healthy subjects and 35 patients with idiopathic dilated cardiomyopathy (IDC). Although cerebral oxyhemoglobin increased during exercise in most of the healthy subjects, oxyhemoglobin decreased during exercise in 15 of 35 patients with IDC. Cerebral oxygenation during exercise and exercise recovery was related to left ventricular function in the patients with IDC.

Background: End-tidal CO2 partial pressure (PETCO2) has been suggested as a noninvasive index reflecting cardiac output under constant ventilation. The aim of this study was to examine whether PETCO2 does reflect cardiac output, even during exercise, in patients with acute myocardial infarction (AMI) undergoing exercise training early after onset. Method and Results Patients aged 47-73 years were randomly assigned to either a training group (n=18) or a control group (n=18) 1 week after the onset of AMI. Those in the training group performed exercise training under supervision at the anaerobic threshold level for 2 weeks, while patients in the control group followed a conventional walking regimen. In the training group, but not in the control group, PETCO2 at the respiratory compensation point increased significantly from 39.1+/-3.5 to 41.1+/-3.7 mmHg (p<0.01). Similarly, the cardiac index at peak exercise increased only in the training group (from 6.04+/-0.98 to 7.31+/-0.97 L/min per m2, p<0.01). These 2 measurements correlated well both before and after the study period. Peak oxygen uptake and anaerobic threshold were increased only in the training group. Conclusions Aerobic exercise training early after the onset of AMI significantly increased PETCO2 during exercise, which may reflect an improvement in cardiac output during exercise in response to physical training via a decreased ventilation-perfusion mismatch.

Background: Atrial fibrillation (AF) is believed to occur first as paroxysmal, then be gradually perpetuated, and finally become chronic as the end result. However, this presumed clinical course has not been well confirmed., Methods and Results: The clinical course of recurrent paroxysmal AF (PAF) from its onset was examined in 171 patients (mean follow-up period: 14.1+/-8.1 years). This study population consisted of patients with no structural heart disease (n=88), ischemic heart disease (n=28), dilated or hypertrophic cardiomyopathy (n=17), valvular heart disease (n=35) or other cardiac diseases. The mean age at the onset of AF was 58.3 +/-11.8 years old. During the mean follow-up period of 14.1 years, PAF eventually developed into its chronic form in 132 patients under conventional antiarrhythmic therapy (77.2%, 5.5% of patients per year). The independent factors for early development into chronic AF were aging (hazard ratio (HR) 1.27 per 10 years, 95% confidence interval (CI) 1.06-1.47)), dilated left atrium (HR 1.39 per 10 mm, 95% CI 1.11-1.69), myocardial infarction (HR 2.33, 95% CI 1.13-4.81), and valvular diseases (HR 2.29, 95% CI 1.22-4.30)., Conclusions: The present long-term observations definitely and quantitatively revealed the progressive nature of PAF.

Background: Reduced variability of the ventricular response interval (VRI) has been reported to predict adverse prognosis in patients with atrial fibrillation (AF). To examine whether it could be related also to the quality of the daily life of patients with AF, the relationships between VRI variability and exercise tolerance, one of the markers for quality of life, were determined in patients with persistent AF., Methods and Results: Thirty-one patients with idiopathic AF were included in the present study. Holter monitoring results and symptom-limited treadmill exercise testing were correlated in these patients without medications for the rate control of AF. The VRI variability, both the SD of the mean R-R interval (SDNN) and the SD of the 5-min mean R-R interval (SDANN), showed significant positive correlation with the exercise capacity (r=0.583, p=0.0004, and r=0.543, p=0.0013, respectively), whereas age, left ventricular ejection fraction and body mass index did not have any significant relationships. Multiple regression analysis revealed that increased SDNN was the only independent predictor of good exercise capacity during the treadmill exercise testing., Conclusions: Increased VRI variability, independently of other clinical variables, can predict good exercise capacity in patients with idiopathic AF, thus being a new sensitive maker for quality of life in AF.

A double product break point (DPBP) occurs simultaneously with both ventilatory threshold (VT) and lactate threshold (LT) in normal subjects. We sought to determine whether a DPBP also occurs in cardiac patients and to investigate correlations between DPBP, VT and LT (study 1). We also evaluated a non-invasive DPBP measurement system that determined blood pressure automatically by the cuff method (study 2). Study 1 comprised 15 patients [8 men and 7 women, mean (SD) age 47.7 (11.1) years] who performed cardiopulmonary exercise tests on a cycle ergometer. The double product was defined as the product of heart rate and direct systolic blood pressure. Arterial blood samples were obtained for measurement of lactate, pyruvate, pH, and norepinephrine levels. VT was determined by gas analysis, and LT was determined as the lactate/pyruvate ratio. DPBPs were detected in all 15 patients. Double product slopes above the DPBP were significantly greater than those below the DPBP (286.2 vs 98.5/W, P<0.001). The lactate/pyruvate ratio increased, arterial pH decreased, and plasma norepinephrine concentration increased above the DPBP. DPBP had strong positive correlations with VT ( r=0.93) and LT ( r=0.95). Study 2 comprised 65 cardiac patients. The DPBP was detected in 89.2% of patients and correlated closely with VT. We conclude that DPBP occurs near VT and LT in cardiac patients during incremental exercise, that the noninvasive DPBP measurement method is comparable to the invasive method, and that DPBP may be as useful an index of exercise intensity in patients with cardiac disease as VT or LT.

Background: Until recently, compensatory mechanisms have been believed to regulate adequately cerebral blood flow in humans. However, this has been called into question by a series of new investigations suggesting that patients with left ventricular dysfunction suffer from cerebral hypoperfusion. We compared cerebral oxygenation during incremental exercise between patients with valvular heart disease and normal subjects., Methods: Thirty-three patients with valvular disease and 33 normal subjects performed a symptom-limited incremental exercise test using a cycle ergometer. Oxyhemoglobin at the forehead was continuously monitored during exercise using near-infrared spectroscopy. Respiratory gas measurements were performed on a breath-by-breath basis., Results: The increase in oxyhemoglobin during exercise was significantly lower in the patients with valvular disease than in normal subjects. The change in oxyhemoglobin during exercise (DeltaO(2)Hb) at the forehead was negatively correlated with the slope of the increase in minute ventilation to the increase in carbon dioxide output (DeltaE/DeltaCO(2)), and positively correlated with the peak oxygen uptake (O(2)), gas exchange threshold (GET), and slope of the increase in O(2) to the increase in the work rate (DeltaO(2)/DeltaWR). Among the patients with valvular disease, 15 patients showed a decrease in oxyhemoglobin at the forehead during exercise. When compared with the patients with increased oxyhemoglobin, those with decreased levels exhibited a higher DeltaE/DeltaCO(2) and a lower peak O(2), GET, and DeltaO(2)/DeltaWR., Conclusions: The present findings strongly suggest that cerebral oxygenation during exercise is dependent on the cardiovascular and pulmonary systems. The study also indicated the presence of cerebral hypoperfusion during exercise in cardiac patients whose cardiac output fails to increase normally.

Background: Atrial fibrillation (AF) is well known as one of the cardiogenic causes for thromboembolism. Although decreased flow and hypercoagulable state of the blood in the fibrillating atrium have been emphasized as the underlying mechanisms, endocardial dysfunction in maintaining the local coagulation balance could also contribute to the thrombogenesis in AF., Methods and Results: The paroxysmal AF model was created by rapid atrial pacing in anesthetized rats. To test the hypothesis that AF induces local coagulation imbalance by disturbing the atrial endocardial function, the gene expression of intrinsic anticoagulant factors, thrombomodulin (TM) and tissue factor pathway inhibitor (TFPI), were determined by means of ribonuclease protection assay, Western blotting, and immunohistochemistry. Rapid atrial pacing for 8 hours significantly decreased TM and TFPI mRNA levels in the left atrium but not in the ventricle, leading to the downregulation of their immunoreactive proteins. Immunohistochemical analysis revealed that TM and TFPI were expressed predominantly in the endocardial cells of the normal atrium, presumably preventing local blood coagulation, and that rapid atrial pacing induced the loss of TM and TFPI expression in the endocardium, leading to deficiency in anticoagulant barriers between the atria and the blood., Conclusions: Rapid atrial pacing acutely downregulated the gene expression of TM and TFPI in the atrial endocardium, thereby inducing local coagulation imbalance on the internal surface of the atrial cavity. These results would support the validity of supplement of anticoagulant molecules deficient in AF.

A patient with 3-vessel coronary artery disease and left ventricular aneurysm underwent coronary artery bypass grafting combined with the Dor approach. Five days later, ventricular tachycardia following short-coupled ventricular premature contractions suddenly occurred and was not responsive to class IB drugs (lidocaine and mexiletine), requiring frequent electrical cardioversion. After the administration of a novel class III drug, nifekalant hydrochloride, this electrical storm of ventricular tachycardia was completely suppressed together with the disappearance of ventricular premature contractions. Nifekalant hydrochloride (MS-551), a pure K(+) channel blocker, might be effective for postoperative recurrent ventricular tachyarrhythmias that are refractory to other antiarrhythmic agents.

Objectives: Physical training in cardiac patients can increase exercise capacity and reduce plasma brain natriuretic peptide(BNP) concentration, but these effects may depend on the etiology of cardiac disease. The change in exercise capacity and BNP during the training period were investigated in patients with different cardiac diseases., Methods: Ninety-one patients after coronary artery bypass grafting(CABG) and 78 patients after valve replacement (VR) underwent a symptom-limited incremental cardiopulmonary exercise test before (1 month) and 6 months after physical training. Anaerobic threshold and peak oxygen uptake(peak-Vo2) were measured during the cardiopulmonary exercise test. Before each cardiopulmonary exercise test, a blood sample was obtained in the resting condition for measuring BNP., Results: Anaerobic threshold and peak-Vo2 were increased significantly from 1 month to 6 months in both groups. BNP in the CABG group indicated a tendency to decrease (194.6 +/- 155.3-->144.2 +/- 232.2 pg/ml, p < 0.1) from 1 month to 6 months. BNP in VR group was significantly decreased (159. 9 +/- 115.5-->112.8 +/- 131.7 pg/ml, p < 0.05) during the training period. The CABG group showed a significant negative correlation between peak-Vo2 and BNP at 1 month(r = -0.28, p < 0.01) and at 6 months(r = -0.39, p = 0.001). The VR group showed a significant negative correlation between peak-Vo2 and BNP at 6 months(r = -0.32, p < 0.01), but not at 1 month., Conclusions: Six months of physical training in patients after cardiac surgery may improve exercise capacity and reduce BNP. BNP concentration in the VR group before physical training did not reflect functional capacity.

Objectives: Power spectral analysis was used to analyze fluctuations of systolic blood pressure and heart rate., Methods: Non-invasive finger plethysmography and electrocardiography were performed in 20 patients with chronic atrial fibrillation and in 10 age-matched healthy subjects with normal sinus rhythm. The impulse train was stored on a personal computer and the power spectrum of R-R interval and systolic blood pressure were obtained by Fourier analysis (0.01-0.03 Hz). The power spectrum (log power vs log frequency) characteristically revealed a linear regression as 1/f beta., Results: The R-R interval spectrum during atrial fibrillation showed a white noise-like flat spectrum when plotted as log power against log frequency, whereas the systolic blood pressure spectrum during atrial fibrillation showed a 1/f noise-like negative slope linear pattern. The spectrum exponent of systolic blood pressure in patients with atrial fibrillation was significantly lower than that in subjects with normal sinus rhythm (2.3 +/- 0.1 vs 1.3 +/- 0.1, p < 0.0001)., Conclusions: Systolic blood pressure fluctuation in patients with atrial fibrillation has a fractal component and is more complex than that of healthy subjects with normal sinus rhythm.

Background: Many cardiac arrhythmias have their own characteristic circadian variations. Because the expression of many genes, including clock genes, is regulated variably during a day, circadian variations of ion channel gene expression, if any, could contribute to the fluctuating alterations of cardiac electrophysiological characteristics and subsequent arrhythmogenesis., Methods and Results: To examine whether cardiac K+ channel gene expression shows a circadian rhythm, we analyzed the mRNA levels of 8 Kv and 6 Kir channels in rat hearts every 3 hours throughout 1 day. Among these channels, Kv1.5 and Kv4.2 genes showed significant circadian variations in their transcripts: approximately 2-fold increase of Kv1.5 mRNA from trough at Zeitgeber time (ZT) 6 to peak at ZT18 and a completely reverse pattern in Kv4.2 mRNA ( approximately 2-fold increase from trough at ZT18 to peak at ZT6). Actually, along with the variations in the immunoreactive proteins, the density of the transient outward and steady-state currents in isolated myocytes and the responses of atrial and ventricular refractoriness to 4-aminopyridine in isolated-perfused hearts showed differences between ZT6 and ZT18, a circadian pattern comparable to that of Kv1.5 and Kv4.2 gene expression. Reversal of light stimulation almost inverted these circadian rhythms, although pharmacological autonomic blockade only partially attenuated the rhythm of Kv1.5 but not of Kv4.2 transcripts., Conclusions: Among all the cardiac K+ channels, Kv1.5 and 4.2 channels are unique in showing characteristic circadian patterns in their gene expression, with Kv1.5 increase during the dark period partially dependent on beta-adrenergic activities and Kv4.2 increase during the light period independent of the autonomic nervous function.

Background: Periodic breathing, an abnormal pattern of respiration consisting of alternating hyperpnea and hypopnea, has been recognized in patients with heart failure. Although fluctuations in pulmonary blood flow have been considered as a possible cause of this type of breathing, its patho-physiological mechanisms are not fully understood. In this study, we sought to determine whether inhaled nitric oxide (NO), a selective pulmonary vasodilator, attenuates periodic breathing., Methods: Eight cardiac patients who exhibited clear oscillatory ventilation while awake (age: 62 +/- 16 years, left ventricular ejection fraction: 48 +/- 20%) were enrolled in the study. After breathing room air (RA) for 15 min, the subjects inhaled air containing 30 ppm of NO for 15 min. Respiratory gas variables including minute ventilation (VE) were measured on a breath-by-breath basis throughout the test., Results: There were no differences in VE (10.7 +/- 1.5 vs. 11.0 +/- 1.7 l/min) or among any of the other hemodynamic or respiratory gas variables studied in the control and NO tests, with the exception of the end-tidal CO(2) partial pressure (5.0 +/- 0.4 vs. 4.8 +/- 0.5%; p = 0.018). The % magnitude of oscillation (i.e., the difference between the peak and nadir of oscillating VE, divided by the mean VE) was 40.0 +/- 22.4% in RA and not influenced by inhaled NO (43.9 +/- 20.8%, p = 0.57)., Conclusion: Inhaled NO at a concentration of 30 ppm did not attenuate periodic breathing in awake patients with mild heart failure.

Objectives: This study assessed the prevalence and clinical background of exercise-induced ventricular tachycardia during exercise testing., Methods: Complications during exercise testing were reviewed in 25,075 consecutive patients, 14,037 men and 11,038 women, who underwent a total of 47,656 maximal treadmill or bicycle exercise tests between April 1985 and March 1999. The mean age of the patients was 53.3 +/- 8.8 (mean +/- SD) years. Non-sustained ventricular tachycardia was defined as 8 or more consecutive ventricular ectopic beats at > 100 beats/min. A total of 126 patients undergoing exercise testing to evaluate the efficacy of pharmacotherapy for ventricular tachycardia were excluded., Results: The major reasons for the exercise test were chest pain (27.0%) and screening (20.3%). Twenty patients (0.08%) had exercise-induced ventricular tachycardia. Six patients had ischemic heart disease, two had cardiomyopathy, five had other cardiac diseases, and seven patients showed no clinical evidence of heart disease. The incidence of ventricular tachycardia in patients with cardiomyopathy (2/109) was higher than in other patients, but the number of patients with ventricular tachycardia was small. Ventricular tachycardia was documented at heart rates of more than 80% of predicted maximal heart rate in 12 of the 20 patients., Conclusions: These results suggest that the exercise testing can be done safely when the end-point criteria are properly applied.

The main mechanism of restenosis after directional coronary atherectomy (DCA) remains obscure. We investigated mechanisms of restenosis after DCA in different coronary artery remodeling patterns. DCA was performed in 51 de novo lesions. The lesions were evaluated by intravascular ultrasound (IVUS) before, immediately after, and 6 months after the procedure. According to the IVUS findings before DCA, we classified the lesions into the following 3 groups: (1) positive (n = 10), (2) intermediate (n = 25), and (3) negative (n = 16) remodeling. We measured lumen area, vessel area, and plaque area using IVUS before DCA, immediately after DCA, and at follow-up. Lumen area increase after DCA was mainly due to plaque area reduction in the positive and intermediate remodeling groups (90 plus minus 15% and 80 plus minus 25% increase in lumen area, respectively), whereas that in the negative remodeling group was due to both plaque area reduction (57 plus minus 22% increase in lumen area) and vessel area enlargement (43 plus minus 33% increase in lumen area). The plaque area increase correlated strongly with late lumen area loss in the positive and intermediate remodeling groups (r = 0.884, p <0.001; r = 0.626, p <0.001, respectively), but the decrease in vessel area was not correlated with lumen area loss. In contrast, both an increase in plaque area and a decrease in vessel area were correlated with late lumen area loss (r = 0.632, p = 0.009; r = 0.515, p = 0.041) in the negative remodeling group. Coronary artery restenosis after atherectomy was primarily due to an increase in plaque in the positive and/or intermediate remodeling groups. However, in the negative remodeling group, late lumen loss might have been caused by both an increase in plaque and vessel shrinkage.

In a patient referred for the evaluation of non-sustained monomorphic ventricular tachycardia on Holter recordings, ventricular fibrillation was electrically induced during electrophysiologic study. Despite the absence of structural heart diseases, his ECG revealed J wave and ST segment elevation in the inferior leads, which showed circadian variation and were augmented by the sodium channel blocker, pilsicainide. This case might lead us to notice a new concept, a 'latent' type of variant Brugada syndrome, and these ECG findings and changes might serve as its diagnostic sign.

A 76-year-old woman with a dual chamber pacemaker underwent coronary intervention of the right coronary artery for unstable angina. After the procedure, she had recurrent chest pain, and after the repeat angiography showed reduced coronary flow in the distal vessel, she underwent emergent coronary artery bypass grafting. During this course of events, the stimulation-excitation interval of the atrium was prolonged and paralleled with the severity of the ischemia. Additionally, a transient but unusual electrophysiological phenomenon was observed that the atrium could be captured at a rate of 90 ppm, but not 80 ppm. This phenomenon might be caused by phase 4 depolarization or rate-dependent facilitation of conduction in the ischemic atrium.

The issue of whether exercise training improves exercise hyperpnea in patients after coronary arterial bypass graft (CABG) surgery has not been fully explored. Effects of short-term physical training on ventilatory response and cardiac output during exercise in patients following coronary arterial bypass grafting surgery is studied. Thirty-four patients underwent exercise training for 2 weeks after the second postoperative week (Ex group); 23 stayed sedentary (Sed group). Ventilatory and cardiac output response during the cardiopulmonary exercise test was measured before and after the training period. The minute ventilation-carbon dioxide output (VE-VCO2) slope decreased from 38.9+/-8.1 to 35.1+/-6.7 (p<0.05) in the Ex group, but failed to decrease in the Sed group (39.7+/-11.1 to 41.5+/-11.4). Cardiac output during exercise at 20W and at peak exercise, and peak oxygen pulse (VO2/HR) increased significantly only in the Ex group after training. There was a correlation between improvement of the VE-VCO2 slope and peak cardiac output during the training interval (r=-0.47) in the Ex group. Short-term physical training after CABG improves ventilatory response to exercise and increases cardiac output during exercise. Improvement of cardiac output is correlated with a decreased value of the VE-VCO2 slope.