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Background: Hypertension is one of the risk factors for cerebro-cardiovascular and renal (CCR) diseases. High blood pressure is affected by the amount of salt (NaCl) and potassium (K) intake. There are many studies reporting the relationship between urinary sodium or potassium excretion and CCR events or all-cause mortality in general populations. Thus, it is necessary to investigate the relationship between urinary NaCl or K excretion and CCR events or all-cause mortality in hypertensive patients under control with anti-hypertensive drugs., Methods: A prospective, multi-center cohort study was performed in 3210 hypertensives under treatment with anti-hypertensive drugs for 5 years. The primary outcome was the CCR events, and the secondary outcome was all-cause mortality. A time-dependent Cox proportional hazards regression analysis was performed to assess the association between outcomes and urinary NaCl and K excretion, blood pressure, or heart rate., Results: During the follow-up period, 61 CCR events and 110 all-cause deaths occurred. There was no association between urinary NaCl excretion and CCR events or all-cause mortality. Lower urinary K excretion and higher Na/K ratio were associated with higher risk of CCR events or all-cause mortality. The CCR events were not associated with systolic, diastolic blood pressure, or heart rate., Conclusion: Lower urinary K excretion was associated with higher risk of CCR events or all-cause mortality in hypertensive patients under treatment with anti-hypertensive drugs., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Rapid percutaneous coronary intervention for acute myocardial infarction (AMI) reduces acute mortality, but there is an urgent need for treatment of left ventricular dysfunction and remodeling after AMI to improve the prognosis. The myocardium itself does not have a high regenerative capacity, and it is important to minimize the loss of cardiomyocytes and maintain the cardiac function after AMI. To overcome these problems, attention has been focused on myocardial regeneration therapy using cells derived from bone marrow. The clinical use of bone marrow stem cells is considered to have low safety concerns based on the experience of using bone marrow transplantation for blood diseases in clinical practice. It has been reported that bone marrow mononuclear cells (BM-MNC) and mesenchymal stem cells (BM-MSC) differentiate into cardiomyocytes both in vitro and in vivo, and they have been considered a promising source for stem cell therapy. To prevent heart failure after human AMI, studies have been conducted to regenerate myocardial tissue by transplanting bone marrow stem cells, such as BM-MSCs and BM-MNCs. Therapies using those cells have been administered to animal models of AMI, and were effective to some extent, but the effect in clinical trials was limited. Recently, it was reported that multilineage-differentiating stress enduring cells (Muse cells), which are endogenous pluripotent stem cells obtainable from various tissues including the bone marrow, more markedly reduced the myocardial infarct size and improved the cardiac function via regeneration of cardiomyocytes and vessels and paracrine effects compared with BM-MSCs. Here, we describe stem cell therapies using conventional BM-MNCs and BM-MSCs, and Muse cells which have potential for clinical use for the treatment of AMI., (Copyright © 2021. Published by Elsevier Ltd.)

Heart failure is the end-stage phenotype of several cardiac diseases. The number of heart failure patients is increasing in accordance with an increase in the number of elderly people. The prognosis of heart failure is poor and its 5-year death rate is comparable to that of stage III cancer. It is important to understand the essential mechanism of the worsening prognosis of heart failure and to practice effective treatment from the perspective of improving the prognosis of heart failure based on its essential mechanism. Plasma noradrenaline level is a good predictor of the survival rate of heart failure patients, and sympathetic nerve activity is augmented in patients with heart failure as evidenced by a higher noradrenaline release rate (spillover) from the sympathetic nerve endings especially in the heart and kidney. Noradrenaline release is regulated by presynaptic receptors at the sympathetic nerve endings, and the kidney affects the sympathetic nerve activity. Although the short-term reflex augmentation of sympathetic nerve activity caused by reduced cardiac function may help to improve cardiac function, long-term augmentation of sympathetic nerve activity damages the heart and deteriorates the prognosis of heart failure. Currently, drugs such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, mineralocorticoid antagonists, ivabradine, angiotensin receptor-neprilysin inhibitor, and sodium-glucose transport protein 2 inhibitors, are used for the treatment of heart failure, and had a good prognosis in large randomized, controlled clinical trials. Interestingly, the same characteristics in common of these drugs is the ability to optimize excessively augmented sympathetic nerve activity. This review discusses insights into essential mechanism of heart failure that determines the prognosis of heart failure, focusing on the interaction between sympathetic nerve activity and anti-heart failure drugs currently recommended by the 2021 guidelines of the Japanese Circulation Society and the Japanese Heart Failure Society for heart failure treatment., Competing Interests: Declaration of Competing Interest There is no conflict of interest to be declared., (Copyright © 2021. Published by Elsevier Ltd.)

Diabetic cardiomyopathy, clinically diagnosed as ventricular dysfunction in the absence of coronary atherosclerosis or hypertension in diabetic patients, is a cardiac muscle-specific disease that increases the risk of heart failure and mortality. Its clinical course is characterized initially by diastolic dysfunction, later by systolic dysfunction, and eventually by clinical heart failure from an uncertain mechanism. Light microscopic features such as interstitial fibrosis, inflammation, and cardiomyocyte hypertrophy are observed in diabetic cardiomyopathy, but are common to failing hearts generally and are not specific to diabetic cardiomyopathy. Electron microscopic studies of biopsy samples from diabetic patients with heart failure have revealed that the essential mechanism underlying diabetic cardiomyopathy involves thickening of the capillary basement membrane, accumulation of lipid droplets, and glycogen as well as increased numbers of autophagic vacuoles within cardiomyocytes. Autophagy is a conserved mechanism that contributes to maintaining intracellular homeostasis by degrading long-lived proteins and damaged organelles and is observed more often in cardiomyocytes within failing hearts. Diabetes mellitus (DM) impairs cardiac metabolism and leads to dysregulation of energy substrates that contribute to cardiac autophagy. However, a "snapshot" showing greater numbers of autophagic vacuoles within cardiomyocytes may indicate that autophagy is activated into phagophore formation or is suppressed due to impairment of the lysosomal degradation step. Recent in vivo studies have shed light on the underlying molecular mechanism governing autophagy and its essential meaning in the diabetic heart. Autophagic responses to diabetic cardiomyopathy differ between diabetic types: they are enhanced in type 1 DM, but are suppressed in type 2 DM. This difference provides important insight into the pathophysiology of diabetic cardiomyopathy. Here, we review recent advances in our understanding of the pathophysiology of diabetic cardiomyopathy, paying particular attention to autophagy in the heart, and discuss the therapeutic potential of interventions modulating autophagy in diabetic cardiomyopathy., (Copyright © 2020. Published by Elsevier Ltd.)

Background: In patients with the long QT syndrome (LQTS), a sudden increase in heart rate can cause T-wave alternans (TWA) with beat-to-beat alternating polarity of T wave. We hypothesized that LQTS patients at high risk for torsades de pointes (TdP) may exhibit momentary atrial or sinoatrial premature beat-induced T-wave inversion (APB-TWI)., Objective: The purpose of this study was to assess the association of APB-TWI with TdP history and with microvolt TWA., Methods: Twenty-four-hour continuous 12-lead electrocardiograms (ECGs) were recorded in 18 healthy subjects and 39 consecutive patients with LQTS types 1 (n = 21), 2 (n = 4), 3 (n = 4), and unidentified (n = 10). Peak TWA was determined by the modified moving average method., Results: The 39 LQTS patients were divided into 2 groups: 10 LQTS patients with TdP history (TdP group) and 29 without (non-TdP group). None of the healthy subjects showed APB-TWI, whereas 38.5% of the LQTS patients (15/39) exhibited APB-TWI. The incidences of APB-TWI and TWA ≥42 μV were significantly higher in the TdP group than in the non-TdP group (APB-TWI: 80% vs 24.1%, P = .006; TWA ≥42 μV: 100% vs 65.5%, P = .04). APB-TWI was inferior in sensitivity for an association with TdP history to TWA ≥42 μV (80% vs 100%) but superior in specificity (75.9% vs 51.7%). Patients with APB-TWI exhibited significantly higher TWA values than those without [median (interquartile range) 73 (55-106.5) vs 48 (37.5-71.8) μV, P = .02]., Conclusion: APB-TWI is an easily measurable ECG pattern and is strongly associated with TdP history as well as TWA ≥42 μV in LQTS patients. APB-TWI and TWA may share pathophysiological mechanisms., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

An 87-year-old man with persistent atrial fibrillation experienced heartburn and dysphagia at 2 years 9 months after initiation of dabigatran. An esophagogastroduodenoscopy demonstrated multiple longitudinal white plaques with ulcers in the narrowed midesophagus compressed between the left atrium and the tortuous aorta. We speculate that the esophageal stenosis contributed to stasis of dabigatran within the esophagus, resulting in prolonged mucosal contact with the caustic contents of the drug. Progressive enlargement of the left atrium may have led to the late onset of the potentially serious complication., (Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Endobronchial ultrasonography (EBUS) facilitates a lung cancer diagnosis. However, qualitative tissue characterization of lung tumors is difficult using EBUS. Integrated backscatter (IBS) is an ultrasound technique that calculates the power of the ultrasound signal to characterize tissue components in coronary arteries. We hypothesized that qualitative diagnosis of lung tumors is possible using the IBS technique. The aim of the present study was to elucidate whether the IBS technique can be used in lung tissue diagnoses., Methods: Thirty-five consecutive patients who underwent surgery for lung cancer were prospectively enrolled. Surgical specimens of the lung and the tumor tissue were obtained, and the IBS values were measured within 48 h after surgery. Histologic images of lung and tumor tissues were compared with IBS values, and the relative interstitial area according to results of Masson's trichrome staining were determined by using an imaging processor., Results: The IBS values in tumor tissue were significantly lower than those in normal lung tissue (-50.9 ± 2.6 dB and -47.6 ± 2.6 dB, respectively; P < .001). The IBS values of adenocarcinomas associated with a good 5-year survival rate were higher than those of non-adenocarcinomas (-48.1 ± 1.6 dB and -52.6 ± 1.4 dB; P < .001). There were significant correlations between the IBS values and the relative interstitial area or micro air area in tumor (r = 0.53 and r = 0.67; P < .01). After combining normal lung tissue and adenocarcinomas with a good prognosis, the sensitivity and specificity for establishing the presence of lung tumors were 84% and 85%., Conclusions: Qualitative diagnosis of lung tumors was possible, with a sensitivity of 84% and a specificity of 85%, using the ultrasound IBS technique., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Echocardiographic parameters to predict pulmonary capillary wedge pressure (PCWP) in mitral regurgitation (MR) are not yet elucidated. We reported that PCWP could be accurately estimated by novel KT index which is defined as log10[left atrial (LA) emptying function (EF)/LA volume]. We examined the usefulness of the KT index as a predictor of PCWP in primary and secondary MR with sinus rhythm and also MR with atrial fibrillation., Methods: LA dimension, strain, volume, EF, and E/e' were measured in moderate to severe MR with sinus rhythm (n=58, age: 67±8 years) and MR with atrial fibrillation (n=24, age: 69±11 years) just before catheterization and in normal subjects (n=26, age: 67±11 years) using speckle tracking echocardiography. MR with sinus rhythm was divided into primary MR (n=27) and secondary MR (n=31). The estimated PCWP (ePCWP) was calculated as 10.8-12.4×KT index., Results: There was a correlation between PCWP and LA dimension, E/e', minimum LA volume index, active LAEF, total LAEF, or LA strain (r=0.32, r=0.31, r=0.55, r=-0.61, r=-0.51, and r=-0.50, respectively, p<0.05). The better correlation was found between PCWP and ePCWP in MR including both primary and secondary MR and also MR with atrial fibrillation (r=0.70, r=0.67, and r=0.58, respectively, p<0.01). Multiple regression analysis revealed that ePCWP was an independent predictor of PCWP in MR. The ePCWP demonstrated good diagnostic accuracy (area under the curve of 0.86) and sensitivity (81%) and specificity (71%) to predict elevated PCWP >15mmHg using a cut-off of 16mmHg., Conclusion: The ePCWP was the reliable echocardiographic parameter to predict PCWP in primary and secondary MR and might also be useful in MR with atrial fibrillation. The ePCWP may have an incremental value in a clinical setting., (Copyright © 2015. Published by Elsevier Ltd.)

Background: The purpose of the present study was to evaluate the tissue characteristics of plaques with moderate or mild stenosis in the inner and outer curvature of the left anterior descending artery (LAD) using integrated backscatter intravascular ultrasound., Methods: We evaluated 66 plaques with moderate stenosis (plaque burden >50% but ≤75%) and 49 plaques with mild stenosis (plaque burden >30% but ≤50%) in 66 patients undergoing percutaneous intervention to the LAD. All plaques were >10mm away from any side branch or previously implanted stents. We divided vessel cross-sections into four quadrants (inner curvature, outer curvature, clockwise lateral side, and counterclockwise lateral side) using the septal branch as a landmark for the inner curvature. We averaged relative lipid area, relative fibrous area, and relative calcified area in minimal lumen area (MLA), three cross-sections proximal to the site of MLA, and three cross-sections distal to the site of MLA., Results: In plaques with moderate stenosis, the relative lipid area in the inner curvature was significantly greater than in the outer curvature and lateral sides, whereas there was no significant difference in plaques with mild stenosis., Conclusion: The present study provides new findings that lipid pool is clustered in the inner curvature and fibrous tissue is clustered in the outer curvature of plaques with moderate stenosis in non-branching LAD lesions., (Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: We conducted a prospective randomized trial to assess the protective effect of continuous intravenous infusion of nicorandil against contrast-induced nephropathy (CIN) in patients with poor renal function., Methods and Results: We randomly assigned 213 patients who would subsequently undergo elective percutaneous coronary intervention (PCI) and who had a high serum cystatin C level to a saline group (n=107) or a nicorandil group (n=106, nicorandil infused in addition to saline for 4h before and 24h after PCI). There were no significant differences in baseline characteristics between the two groups. However, the average percent increases in serum creatinine and cystatin C following PCI were significantly smaller in the nicorandil group than the saline group. Likewise, the average percent decline in the estimated glomerular filtration rate was smaller in the nicorandil group. Correspondingly, the incidence of CIN was dramatically lower in the nicorandil group than the saline group (2.0% vs. 10.7%, p<0.02). Univariate regression analysis revealed nicorandil treatment to be the only significant predictor of CIN development (odds ratio: 0.173, 95% confidence interval: 0.037-0.812, p=0.026)., Conclusions: Nicorandil strongly prevents CIN in patients with poor renal function undergoing PCI., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: We hypothesized that a development of a novel index based on the combination of left atrial volume (LAV) and left atrial (LA) function evaluated by the time-LA volume curve using speckle tracking echocardiography (STE) would be accurate and useful to estimate pulmonary capillary wedge pressure (PCWP). Our goal was to develop a novel index of PCWP based on a combination of LAV and LA function using STE., Methods: A cross-validation study was performed with the patients divided into a training study to define the novel index (n=50) and a testing study to validate the index (n=196). PCWP was measured by right heart catheterization, and phasic LAV and emptying function (EF) were measured by STE., Results: Simple linear regression analysis in the training study revealed that the novel index that best estimated PCWP was the kinetics-tracking index [KT index=log10 (active LAEF/minimum LAV index)]. Multiple regression analysis revealed that the KT index was the most reliable predictor of PCWP. It had the strongest correlation with PCWP (r=-0.86, p<0.001) among all echocardiographic parameters. In the testing study, PCWP estimated by the KT index was also strongly correlated with measured PCWP (r=0.92, p<0.001). These correlations were also strong in the patients with reduced left ventricular ejection fraction (<50%), chronic heart failure, and chronic atrial fibrillation (r=0.92, r=0.91, r=0.79, p<0.001, respectively)., Conclusions: A novel index (KT index) using a combination of LAV and LA function was a powerful and useful predictor of PCWP and may be valuable in routine clinical practice., (Copyright © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Treatment with granulocyte colony-stimulating factor (G-CSF) reportedly mitigates postinfarction cardiac remodeling and dysfunction. We herein examined the effects of G-CSF knockout (G-CSF-KO) on the postinfarction remodeling process in the hearts of mice. Unexpectedly, the acute infarct size 24 hours after ligation was similar in the two groups. At the chronic stage (4 weeks later), there was no difference in the left ventricular dimension, left ventricular function, or histological findings, including vascular density, between the two groups. In addition, expression of vascular endothelial growth factor (VEGF) was markedly up-regulated in hearts from G-CSF-KO mice, compared with wild-type mice. Microarray failed in detecting up-regulation of VEGF mRNA, whereas G-CSF administration significantly decreased myocardial VEGF expression in mice, indicating that G-CSF post-transcriptionally down-regulates VEGF expression. When G-CSF-KO mice were treated with an anti-VEGF antibody (bevacizumab), cardiac remodeling was significantly aggravated, with thinning of the infarct wall and reduction of the cellular component, including blood vessels. In the granulation tissue of bevacizumab-treated hearts 4 days after infarction, vascular development was scarce, with reduced cell proliferation and increased apoptosis, which likely contributed to the infarct wall thinning and the resultant increase in wall stress and cardiac remodeling at the chronic stage. In conclusion, overexpression of VEGF may compensate for the G-CSF deficit through preservation of cellular components, including blood vessels, in the postinfarction heart., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

We investigated the effect of restriction of food intake, a potent inducer of autophagy, on postinfarction cardiac remodeling and dysfunction. Myocardial infarction was induced in mice by left coronary artery ligation. At 1 week after infarction, mice were randomly divided into four groups: the control group was fed ad libitum (100%); the food restriction (FR) groups were fed 80%, 60%, or 40% of the mean amount of food consumed by the control mice. After 2 weeks on the respective diets, left ventricular dilatation and hypofunction were apparent in the control group, but both parameters were significantly mitigated in the FR groups, with the 60% FR group showing the strongest therapeutic effect. Cardiomyocyte autophagy was strongly activated in the FR groups, as indicated by up-regulation of microtubule-associated protein 1 light chain 3-II, autophagosome formation, and myocardial ATP content. Chloroquine, an autophagy inhibitor, completely canceled the therapeutic effect of FR. This negative effect was associated with reduced activation of AMP-activated protein kinase and of ULK1 (a homolog of yeast Atg1), both of which were enhanced in hearts from the FR group. In vitro, the AMP-activated protein kinase inhibitor compound C suppressed glucose depletion-induced autophagy in cardiomyocytes, but did not influence activity of chloroquine. Our findings imply that a dietary protocol with FR could be a preventive strategy against postinfarction heart failure., (Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Three-dimensional speckle tracking echocardiography (3D-STE) has a major advantage in the improvement of accuracy in the evaluation of cardiac chamber volume without any geometrical assumption. Thus, the aim of this study was to use 3D-STE to elucidate the features of left atrial (LA) volume and function that are altered by hypertension (HTN) by comparing well-controlled HTN patients with normal subjects., Methods: Conventional echocardiographic parameters and LA phasic volume and function were measured from apical view by 3D-STE in 40 patients with well-controlled HTN [systolic blood pressure (BP) <140 and diastolic BP <90mmHg for more than one year] and 40 normotensive subjects., Results: The passive LA emptying function (EF) in the patients with well-controlled HTN significantly decreased (16±7% vs. 22±8%, p=0.0013) and the active LAEF in patients with well-controlled HTN significantly increased (35±10% vs. 30±9%, p=0.029) compared with the values in normotensive subjects. Multivariate logistic regression analysis revealed that E/e' was an independent determinant of well-controlled HTN. The maximum LA volume index was correlated with elevated E/e' (r=0.30, p=0.0064), whereas the maximum LA volume index was not correlated with LV mass index or systolic BP. This change was independent of age., Conclusions: These results suggest that LV diastolic dysfunction occurs before structural changes of left atrium and left ventricle even in patients with well-controlled HTN., (Copyright © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Hyogo is the second prefecture, after Kanagawa, to enact a smoking ban in public places in Japan. The effect of this smoking ban on acute coronary syndrome (ACS) has not been evaluated., Purpose: Changes in the annual number of ACS hospital cases in Hyogo Prefecture, before and after the enactment of the prefectural legislative ban on smoking in public places, are to be compared with those in Gifu Prefecture, where there is no smoking-ban legislation., Methods: Consecutive Hyogo residents with ACS, admitted to 33 major hospitals in the Hanshin-Awaji-Kobe district, which covers 56% of the population, during the 12 months before implementation of the legislation (April 2012 through March 2013) and during the same 24 months thereafter (April 2013 through March 2015) will be enrolled. Consecutive patients with ACS, who are Gifu residents, treated at the 20 major hospitals in Gifu Prefecture will be enrolled as geographical controls. The primary endpoint is the change in number of ACS admissions from April 2012 through March 2015, considering the periods before and after the smoking-ban legislation in Hyogo prefecture., Conclusion: Our study has certain strengths: (1) This is the first large Japanese study of ACS registry with smoking-ban legislation. (2) Major hospitals in the Hanshin-Awaji-Kobe district are included. (3) The data will cover 3 years including 1 year before legislation enactment. (4) The data will be compared with those of Gifu Prefecture, where smoking-ban legislation will not be enacted. (5) The very large database makes possible analysis of subgroups based on age and gender., (Copyright © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

It has been suggested that apoptosis may be responsible for a significant amount of the cardiomyocyte death that contributes to the development and progression of heart failure. However, studies of actual heart disease and in vivo experimental models have provided little or no direct morphological evidence that cardiomyocyte apoptosis occurs at any stage of heart failure, despite the availability of much indirect evidence that includes detection of DNA fragmentation and apoptosis-related factors. The Nomenclature Committee on Cell Death (NCCD), an international organization consulting on cell death, proposed an international standard for the definition and classification of cell death, in which cell death was defined based purely on morphological criteria. This is because there is no clear-cut equivalence between ultrastructural alterations and biochemical cell death characteristics. This review will first introduce the NCCD definition and classification of cell death and, based on this classification, survey the available data from both animals and humans to critically assess the impact of cardiomyocyte apoptosis during the progression of heart failure of various etiologies. Particularly noteworthy is the wide variation in the reported rates of apoptosis--e.g., the difference was >1000-fold in one heart failure model--but even more importantly, no morphological (ultrastructural) data has ever been shown definitively demonstrating apoptosis of a cardiomyocyte. We conclude from our survey that even the existence of cardiomyocyte apoptosis in heart failure remains controversial., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: The aim of this study was to validate the accuracy of three-dimensional (3D) speckle tracking echocardiography (STE) and two-dimensional (2D)-STE for the assessment of left atrial (LA) volume and function by comparison with 3D-computed tomography (CT) performed on the same day as STE., Methods: LA phasic volume and emptying function (EF) were measured in 28 patients with paroxysmal atrial fibrillation undergoing catheter ablation (62±11 years old) using both 3D-STE and 2D-STE during sinus rhythm. LA phasic volume and function measured by 3D-STE and 2D-STE were validated using 3D-CT as a gold standard., Results: The intraobserver correlation coefficient and variability in maximum LA volume assessed by 3D-STE were 0.99 and 1.4±6.0%, respectively. The interobserver correlation coefficient and variability in maximum LA volume assessed by 3D-STE were 0.99 and 0.2±4.5%, respectively. There were strong correlations between LA phasic volume measured by 3D-CT and those measured by 3D-STE (r=0.98, p<0.001). There were correlations between LA phasic function measured by 3D-CT and those measured by 3D-STE (r=0.85-0.88, p<0.001). There was a better agreement between 3D-CT and 3D-STE in the assessment of LA phasic volumes and function than between 3D-CT and 2D-STE in apical 2- and 4-chamber view., Conclusions: 3D-STE allows more accurate measurement of LA volume and function than 2D-STE and has high reproducibility., (Copyright © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

We investigated the effect of resveratrol, a popular natural polyphenolic compound with antioxidant and proautophagic actions, on postinfarction heart failure. Myocardial infarction was induced in mice by left coronary artery ligation. Four weeks postinfarction, when heart failure was established, the surviving mice were started on 2-week treatments with one of the following: vehicle, low- or high-dose resveratrol (5 or 50 mg/kg/day, respectively), chloroquine (an autophagy inhibitor), or high-dose resveratrol plus chloroquine. High-dose resveratrol partially reversed left ventricular dilation (reverse remodeling) and significantly improved cardiac function. Autophagy was augmented in those hearts, as indicated by up-regulation of myocardial microtubule-associated protein-1 light chain 3-II, ATP content, and autophagic vacuoles. The activities of AMP-activated protein kinase and silent information regulator-1 were enhanced in hearts treated with resveratrol, whereas Akt activity and manganese superoxide dismutase expression were unchanged, and the activities of mammalian target of rapamycin and p70 S6 kinase were suppressed. Chloroquine elicited opposite results, including exacerbation of cardiac remodeling associated with a reduction in autophagic activity. When resveratrol and chloroquine were administered together, the effects offset one another. In vitro, compound C (AMP-activated protein kinase inhibitor) suppressed resveratrol-induced autophagy in cardiomyocytes, but did not affect the events evoked by chloroquine. In conclusion, resveratrol is a beneficial pharmacological tool that augments autophagy to bring about reverse remodeling in the postinfarction heart., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Left atrial appendage (LAA) thrombus increases the risk of thromboembolism in atrial fibrillation (AF), and LAA contractile function like emptying fraction (EF) should have physiological importance in thrombus formation. The aim of this study was to validate a velocity vector imaging (VVI) method for quantification of the LAA function and to elucidate echocardiographic parameters that are related to the presence of LAA thrombus in patients with nonvalvular AF., Methods: We measured left atrial (LA) dimension and LAEF by VVI using transthoracic echocardiography, and LAA emptying velocity, spontaneous echo contrast (SEC), and LAAEF by VVI using transesophageal echocardiography (TEE) in 142 consecutive patients with nonvalvular AF. The patients were divided into two groups according to the presence (n=38) or absence (n=104) of LAA thrombus., Results: There was a good correlation between the VVI method and manual-tracing method for LAAEF and LAEF of patients with AF (r=0.97, r=0.96, respectively, p<0.001). LAAEF in AF with thrombus was significantly reduced compared with AF without thrombus (16.9±3.1% and 29.0±9.7%, p<0.001). In multivariate logistic regression analysis, LAAEF, SEC, and prior stroke were independent determinants of LAA thrombus. Using 20% of LAAEF as a cutoff value, the sensitivity was 92% and specificity was 88% for LAA thrombus., Conclusion: The VVI method was reliable in the measurement of LAAEF and LAEF compared with the manual-tracing method. LAAEF assessed by the VVI method using TEE was related to the presence of LAA thrombus., (Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Unstable carotid plaques are associated with an increased incidence of embolic complications after carotid artery stenting (CAS) or carotid endarterectomy (CEA). The aim of this study was to elucidate the relationship between the tissue components of carotid plaques and the incidence of new ipsilateral silent ischemic lesions (NISIL) after CAS or CEA., Methods: We performed CAS in 56 patients and CEA in 25 patients. We also performed quantitative analyses of carotid plaque characteristics before treatment using T1 weighted black-blood magnetic resonance imaging (BB-MRI). The signal intensity ratio (SIR) was defined as the ratio of signal intensity evaluated by BB-MRI in carotid plaques to that of sternocleidomastoid muscle. According to criteria that we and other investigators previously reported, an SIR ≥ 1.25 was defined as "high". NISIL were evaluated by diffusion-weighted imaging of MRI before and after CAS or CEA., Results: In the high SIR group, the incidence of NISIL was significantly greater after CAS than after CEA (61% vs 13%, respectively, p=0.006), whereas there were no significant difference in NISIL after the two procedures when the SIR was <1.25 (21% vs 0%). In multivariate regression analysis, the independent predictors of NISIL were CAS (p=0.002), symptomatic stenosis (p=0.036) and the SIR (p=0.049)., Conclusions: Noninvasive quantitative tissue characterization of carotid plaques using BB-MRI is useful to determine the indication for CAS., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Tissue characteristics of coronary plaques can be evaluated using integrated backscatter intravascular ultrasound (IB-IVUS), while fractional flow reserve (FFRmyo) is an index of functional coronary stenosis. We assessed the relation between functional stenosis and the characteristics of plaque tissue using FFRmyo and IB-IVUS., Methods and Results: A total of 17 lesions with 75%-stenosis assessed visually by coronary angiography from 17 stable angina patients (64.2+/-9.1 years old, 11 males) were studied. IB-IVUS was evaluated in the most stenotic cross-sectional area. Using commercially available software, coronary plaques were assessed for calcification (CA), fibrosis (F), and lipid pool (LP). Lesions were localized in the left anterior descending artery in 11 patients, the left circumflex in 3, and the right coronary artery in 3. On quantitative coronary angiography, the percent diameter stenosis (%DS) was 60.5+/-7.3%. Plaque burden was 71.4+/-9.1%, FFRmyo was 0.74+/-0.13. The tissue component of the plaques was: CA(%), 3.0+/-2.4%; F(%), 60.5+/-9.6%; LP(%), 37.2+/-11.0%. Significant correlation was not observed between %DS or plaque burden and FFRmyo, structural stenosis and plaque characterization, nor between CA(%) and FFRmyo. There was a positive correlation between F(%) and FFRmyo (r=0.62, p<0.01) and a negative correlation between LP(%) and FFRmyo (r=-0.52, p<0.05)., Conclusion: Our findings indicate that the tissue characteristics of coronary plaques in intermediate lesion affect functional stenosis., (Copyright 2009 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Activation of Fas signaling is a key mediator of doxorubicin cardiotoxicity, which involves both cardiomyocyte apoptosis and myocardial inflammation. In this study, acute cardiotoxicity was induced in mice by doxorubicin, and some mice simultaneously received an intramuscular injection of adenoviral vector encoding mouse soluble Fas (sFas) gene (Ad.CAG-sFas), an inhibitor of Fas/Fas ligand interaction. Two weeks later, left ventricular dilatation and dysfunction were apparent in the LacZ-treated control group, but both were significantly mitigated in the sFas-treated group. The in situ nick-end labeling-positive rate were similar in the two groups, and although electron microscopy revealed cardiomyocyte degeneration, no apoptotic structural features and no activation of caspases were detected, suggesting an insignificant role of apoptosis in this model. Instead, sFas treatment reversed doxorubicin-induced down-regulation of GATA-4 and attenuated ubiquitination of myosin heavy chain and troponin I to preserve these sarcomeric proteins. In addition, doxorubicin-induced significant leukocyte infiltration, fibrosis, and oxidative damage to the myocardium, all of which were largely reversed by sFas treatment. sFas treatment also suppressed doxorubicin-induced p53 overexpression, phosphorylation of c-Jun N-terminal kinase, c-Jun, and inhibitor of nuclear factor-kappaB, as well as production of cyclooxygenase-2 and monocyte chemoattractant protein-1, and it restored extracellular signal-regulated kinase activation. Therefore, sFas gene therapy prevents the progression of doxorubicin-induced acute cardiotoxicity, with accompanying attenuation of the cardiomyocyte degeneration, inflammation, fibrosis, and oxidative damage caused by Fas signaling.

Objective: A major concern with carotid artery stenting (CAS) is the potential for cerebral embolism. The purpose of this study was to determine whether integrated backscatter (IBS) ultrasound and black-blood magnetic resonance imaging (BB-MRI) can predict the risk of a silent ischemic lesion after CAS., Methods: We performed quantitative analysis of plaque characteristics in carotid arteries using IBS ultrasound and BB-MRI before CAS in 50 patients. We measured IBS values and the signal intensity ratio (SIR) from T1 weighted images of all plaques. We also performed diffusion-weighted (DWI) MRI of the brain before and after CAS., Results: In the patient group that was positive (n=19) for newly appearing ipsilateral silent ischemic lesions (NISIL), relative unstable component area (%UCA) evaluated by IBS analysis (60.2+/-23.4% and 35.3+/-19.2%, p<0.001) and SIR (1.40+/-0.19 and 1.18+/-0.25, p<0.01) in most stenotic lesions were higher than in the NISIL-negative group (n=31). From the analysis of receiver operating characteristic curves, 50% of the %UCA measured by IBS and an SIR of 1.25 measured by BB-MRI were the most reliable cutoff values for predicting NISIL. In multivariate logistic regression analysis, the independent predictors of NISIL were SIR (p=0.030), the CRP level (p=0.041) and the %UCA measured by IBS (p=0.049)., Conclusions: Quantitative tissue characterization of carotid plaques using IBS ultrasound and BB-MRI was useful to predict NISIL after CAS. The plaque components in carotid arteries should be evaluated by BB-MRI or IBS ultrasound before CAS to improve the clinical outcome of this procedure., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The purpose of this study was to elucidate the usefulness of integrated backscatter (IBS) transesophageal echocardiography (TEE) for the evaluation of atrial degeneration and clarify whether atrial degeneration predicts the occurrence of atrial fibrillation (AF)., Background: One of the causes of AF is pathological degeneration of the left atrium (LA). However, there is no appropriate method to evaluate degeneration of the LA in the clinical setting., Methods: The IBS images were acquired with TEE with a 4- to 7-MHz transducer. The IBS values were calculated as the average power of the backscattered signal from regions of interest (ROI). In the pathological study, we measured IBS values of 21 left atrial specimens obtained from 10 autopsied hearts. Relative interstitial area in the ROI was automatically calculated by a personal computer. In the clinical study, we measured IBS values of the entire LA wall at 5-mm intervals (except the posterior wall) in 42 patients (18 non-AF patients, 14 paroxysmal AF patients, and 10 chronic AF patients). Each IBS value was color-coded to construct 3-dimensional maps., Results: There was a weak correlation between the relative interstitial area and IBS values (r = 0.45, p = 0.038). Average corrected IBS values of total voxels in color-coded maps in the AF group (24.4 +/- 6.4 dB) and the paroxysmal AF group (23.9 +/- 9.6 dB) were significantly greater than those in the non-AF group (15.6 +/- 7.4 dB, p = 0.007), whereas there was no significant difference in LA diameter between the paroxysmal AF group (39.4 +/- 6.5 mm) and the non-AF group (36.7 +/- 5.5 mm)., Conclusions: With IBS-TEE, we can identify an increase in atrial degeneration that might predict the occurrence of AF before LA dilation.

To examine the functional significance and morphological characteristics of starvation-induced autophagy in the adult heart, we made green fluorescent protein-microtubule-associated protein 1-light chain 3 (LC3) transgenic mice starve for up to 3 days. Electron microscopy revealed round, homogenous, electron-dense lipid droplet-like vacuoles that initially appeared in cardiomyocytes as early as 12 hours after starvation; these vacuoles were identified as lysosomes based on cathepsin D-immunopositive reactivity and acid phosphatase activity. The increase in the number of lysosomes depended on the starvation interval; typical autophagolysosomes with intracellular organelles also appeared, and their numbers increased at the later phases of starvation. Myocardial expression of autophagy-related proteins, LC3-II, cathepsin D, and ubiquitin, increased, whereas both myocardial ATP content and starvation integral decreased. Treatment with bafilomycin A1, an autophagy inhibitor, did not affect cardiac function in normally fed mice but significantly depressed cardiac function and caused significant left ventricular dilatation in mice starved for 3 days. The cardiomyocytes were occupied with markedly accumulated lysosomes in starved mice treated with bafilomycin A1, and both the myocardial amino acid content, which was increased during starvation, and the myocardial ATP content were severely decreased, potentially contributing to cardiac dysfunction. The present findings suggest a critical role of autophagy in the maintenance of cardiac function during starvation in the adult.

Objective: Statins have been reported to be protective against myocardial infarction (MI). Moreover, statin drugs upregulate nitric oxide (NO) in coronary artery independent of lipid-lowering effects. However their precise mechanism for MI-protection is unclear. We investigated the effect of lipophilic statin administration in a normocholesterolemic rabbit MI model., Methods: Nω-nitro-L-arginine methylester (L-NAME, 10 mg/kg) or vehicle alone was intravenously administered 20 min before inducing ischemia, followed by intravenous administration of simvastatin (5 mg/kg) or saline 10 min before ischemia. Rabbits then underwent 30 min of coronary occlusion followed by 48 h of reperfusion. The at-risk and infarct areas were calculated as a percentage of the total left ventricular slice area., Results: Determination of infarct size revealed that pre-ischemic treatment with simvastatin reduced infarct size (30.5 ± 4%) in comparison to controls (45.0 ± 3%) (P < 0.05). This infarct size-reducing effect of simvastatin could be completely abrogated by pretreatment with L-NAME (42.0 ± 4%)., Conclusions: Pre-ischemic treatment with simvastatin reduces MI size via NO production. Simvastatin could be a useful drug for coronary artery disease patients without dyslipidemia as it has direct protective effects.

A 75-year-old man underwent PCI for a bifurcation lesion with 90% stenosis in segment 6 and 75% proximal stenosis in segment 9 of the left coronary artery. We implanted a Duraflex coronary stent into segment 6 and kissing balloon inflation for segments 6 and 9. Although these 2 lesions were adequately dilated, we noticed coronary perforation caused by the guide wire in a small branch of segment 9. We tried to repair the perforation using a small balloon and long inflation, but unfortunately the perforation was not improved. We attempted to occlude the small branch including the perforation site with an autologous blood clot via a wire microcatheter inserted into the small branch. The autologous blood clot was suspended in contrast media and saline. Using this procedure, the small branch of segment 9 was occluded completely and the perforated site was repaired. After the procedure, no significant CPK elevation was detected, and 6 months later, we confirmed that small branch embolization was improved and coronary flow was good. Autologous blood clot is useful to occlude and repair perforations in small side branches of the coronary artery without myocardial damage.

Background: Aspirin and anti-platelet drugs are used commonly for patients with coronary heart disease. Proton pump inhibitor (PPI) and high-dose H2-blocker were recommended for preventing NSAIDs-related ulcer. Previously H2-blocker reported to have some negative cardiovascular effects. Additionally, a recent in vitro study showed that PPI reduced cardiac contractility. In this study, we evaluated whether chronic administration of PPI and high-dose H2-blocker affects left ventricular function., Method: Fifty-two stable angina patients were enrolled and classified into PPI group ([P]; lansoprazole: 15 mg/day, n=28), H2-blocker group ([H]; famotidine: 40 mg/day, n=8), and control ([C]; none or mucosal-defense drug, n=16). Eligible patients showed normal cardiac function in initial catheterization without administrated PPI or H2-blocker. They received percutaneous coronary intervention and follow-up catheterization. We compared changes in ejection fraction (EF: %), end diastolic/systolic volume index (EDVI/ESVI: ml/m(2)), and peak positive/negative dp/dt (+/-dp/dt: mmHg/s) in left ventricular angiography series., Result: There were no significant differences among three groups regarding patient characteristics, backgrounds of angiographic and intervention, except for fewer smokers in [C]. Other drugs such as beta- and Ca-blocker did not have effects on cardiac function except for aspirin during 255+/-115 days follow-up. Rate of EF changes significantly decreased in [P], and tended to decrease in [H] (C: 3.8+/-9.8%, H: -1.6+/-7.6%, P: -2.1+/-5.9%; p<0.05 for [C] vs. [P]). Those of ESVI changes were significantly greater in [P], and tended to be greater in [H] (C: -4.5+/-16.2%, H: 4.9+/-15.5%, P: 7.3+/-16.2%; p<0.05 for [C] vs. [P]), though, EDVI changes' were similar (C: 2.5+/-8.9%, H: 2.6+/-3.6%, P: 1.6+/-6.1%; p=ns). Rate of +/-dp/dt-changes tended to decrease in [H] (+dp/dt: C: 3.9+/-15.5%, H: -10.0+/-25.2%, P: 0.3+/-19.6%; p=ns, -dp/dt: C: -0.1+/-19.5%, H: -8.5+/-20.4%, P: 5.7+/-27.7%; p=ns)., Conclusion: In this study, PPI and high-dose H2-blocker have EF-reducing tendency. However, these changes were small and these drugs seemed to exhibit little influence clinically.

Objectives: Treatment of mitral valve stenosis with catheter balloon commissurotomy (CBC) yields acceptable immediate results even when one commissure shows calcification. However, the long-term outcomes in such cases remain unclear., Methods: We examined the immediate and long-term (mean: 11+/-5 years) outcomes of 57 patients who underwent 58 CBC procedures. Patients were classified into group A (no commissural calcification, n=44) or group B (unilateral commissural calcification, n=13). From the appearance of the mitral valve just after CBC, commissurotomy was judged to be bilateral, incomplete, or excessive. End points were death, recurrence of congestive heart failure necessitating hospitalization, embolism, repeat CBC, or mitral valve replacement., Results: There were significant numbers of unfavorable mitral valve morphologies evaluated according to Sellors classification, estimated by echocardiograms; Sellors class I: 20 patients in group A vs. none in group B (p<0.05). Class II: 24 in group A vs. 10 in group B. and class III: none in group A vs. 3 in group B (p<0.05). CBC increased the mitral valve area (Gorin formula) from 1.3+/-0.3 to 2.1+/-0.5 cm2 in patients in group A and from 1.1+/-0.2 to 1.8+/-0.4 cm2 in those in group B (p=n.s.). Among the latter, there were significantly more excessive commissurotomies than in group A and no bilateral commissurotomy. The overall or event-free survival rate during the follow-up of group B showed a lower tendency than in group A (overall: group A: 86.2% vs. group B: 84.6%, p, n.s. event-free: 56.8% vs. 46.2%, respectively, p=n.s.). Univariate predictors of all events in group B included post-CBC pulmonary arterial pressure, and the pattern of commissurotomy after CBC (p<0.05). Excessive commissurotomy increased clinical events some years later, after the procedure., Conclusions: In this study, involving a small number of subjects, long-term outcomes of patients with unilateral commissural calcification receiving CBC showed no significant difference as compared to those with commissural calcification absence. However, it is necessary to perform careful follow-up of CBC patients with unilateral commissural calcium.

In UM-X7.1 hamster model of human dilated cardiomyopathy, heart failure progressively develops and causes 50% mortality by 30 weeks of age. Through ultrastructural analysis, we found that many cardiomyocytes of this model contain typical autophagic vacuoles including degraded mitochondria, glycogen granules, and myelin-like figures. In addition, ubiquitin, cathepsin D, and Rab7 were overexpressed as determined by immunoassays. Importantly, most cardiomyocytes with leaky plasma membranes were positive for cathepsin D, suggesting a direct link between autophagic degeneration and cell death. Meanwhile, cardiomyocyte apoptosis appeared insignificant. Granulocyte colony-stimulating factor (10 microg/kg/day), injected 5 days/week from 15 to 30 weeks of age, improved survival among 30-week-old hamsters (100% versus 53% in the untreated hamsters, P < 0.0001); ventricular function and remodeling, increased cardiomyocyte size, and reduced myocardial fibrosis followed by a dramatic reduction in the autophagic findings were also seen. Granulocyte colony-stimulating factor also down-regulated tumor necrosis factor-alpha and increased activities of Akt signal transducer and activator of transcription-3, and matrix metalloproteinases. However, there was no clear evidence of transdifferentiation from bone marrow cells into cardiomyocytes. In conclusion, autophagic death is important for cardiomyocyte loss in the cardiomyopathic hamster, and the beneficial effect of granulocyte colony-stimulating factor acts mainly via an anti-autophagic mechanism rather than anti-apo-ptosis or regeneration.

We examined a possible preventive effect of Linderae radix (LR), the root of Lindera strychnifolia, on the progression of diabetic nephropathy. Water extract of Linderae radix (LR extract) was orally administered to the C57BL/KsJ-db/db (db/db) mice, a model of genetic diabetes, at a dose of 730 mg/kg/day for 12 week. The LR extract treatment did not affect glucose metabolism and systolic pressure. However, it resulted in a better renal function as evaluated by creatinine clearance (Ccr) and serum creatinine than the control; Ccr and serum creatinine were progressively worsened in controls (0.13+/-0.01 (l/day) and 0.69+/-0.04 (mg/dl), respectively) whereas unchanged in the treated group (0.24+/-0.03 (l/day), p<0.05 and 0.53+/-0.04 (mg/dl), p<0.05, respectively). Kidneys of the LR extract-treated group showed glomeruli with greater area and cell population, smaller glomerular sclerotic index, and less fibrosis in glomeruli, where apoptotic rate of glomerular cells were decreased compared with the control kidneys. Furthermore, renal TGF-beta(1) expression was decreased in the LR extract-treated group. These findings suggest that the LR therapy can be a novel therapeutic approach against diabetic nephropathy.

Background: DNA breaks detected largely by terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate in situ nick end-labeling (TUNEL) are observed in the hearts of patients with diseases such as dilated cardiomyopathy (DCM)., Study Objectives: To determine the prognostic value of TUNEL assays in cases of DCM., Design, Setting, and Participants: DCM patients were selected from among patients who had undergone left ventricular (LV) biopsy during the period from 1994 to 2001 in our hospital. Of those, 46 (35 men and 11 women; mean [+/- SD] age, 58 +/- 11 years) who were followed up for > 3 years after the undergoing the biopsy (mean follow-up period, 4.9 +/- 2.0 years) or died during the follow-up period were entered into the present study. The myocardial apoptotic index was assessed in deparaffinized biopsy specimens that were stained using a conventional TUNEL assay. In addition, all surviving patients received a follow-up echocardiographic examination., Results: Ten of the 46 biopsy specimens (22%) contained TUNEL-positive myocytes; their mean apoptotic index was 0.44 +/- 1.05%. The apoptotic index showed no relation to cardiac functional parameters determined at the time of biopsy, however. Seven patients died during the follow-up period, and 19 of the surviving patients were readmitted to the hospital because of a worsening of their heart failure. There was no significant difference in the apoptotic indexes of biopsy specimens from the dead and surviving patients, or between the surviving patients who were readmitted to the hospital and those who were not. There was also no significant correlation between the apoptotic index and changes in the LV ejection fraction, LV end-diastolic diameter, or LV posterior wall thickness during follow-up., Conclusion: The apoptotic index derived from TUNEL assays is not predictive of the prognosis of patients with DCM-induced heart failure.

Recently, ultrasound tissue characterization of the carotid arteries with an integrated backscatter (IB) analysis was shown to identify a high-risk group of atherosclerosis. To clarify whether IB ultrasound is useful in assessing arterial sclerosis as well as stiffness beta and whether IB values reflect the histological structure, we measured IB values of common carotid media in 52 subjects without coronary risk factors and in 10 patients with systemic sclerosis (SSc) in the clinical studies and 12 patients in the histological studies with a Philips Medical Systems Sonos 5500. IB values were correlated with age (r=0.69, P<0.0001), intima-media thickness (r=0.72, P<0.0001) and stiffness beta (r=0.80, P<0.0001) in the control subjects. IB values and stiffness beta in the SSc group were greater than in an age- and sex-matched control group (IB values: 9.6+/-2.7dB versus 16.1+/-1.8dB; stiffness beta: 11.5+/-4.5 versus 20.6+/-5.6, P<0.01). IB values of the media were correlated with the elastic fragmentation index (r=0.63, P=0.029) and the collagen fiber index (r=0.59, P=0.046). Measurements of IB values of carotid media are useful for non-invasively evaluating arterial sclerosis.

Dynamic process of apoptosis has not been elucidated in adult rat cardiomyocytes. Soluble Fas ligand (0.1 microg/ml) in the presence of actinomycin D (0.05 microg/ml) induced apoptosis in cultured adult rat cardiomyocytes, as documented by activated caspase-3, DNA fragmentation, and apoptotic ultrastructure. In the present model, we observed 60 adult cardiomyocytes with a normal rod shape under a real-time videomicroscope continuously for 48 hours. Seventeen cells (28%) were unchanged and 7 cells (12%) showed oncosis (so-called necrosis) in which no beating was evident. In the remaining 36 cells (apoptosis, 60%), a slow beating (17 +/- 3/min) was initiated 16 +/- 1 hours later. Approximately 1 hour later, the rod cells showed long-axial shortening as bone- or club-like, or square-shaped, accompanied with faster beating rates (35 +/- 7/min). In 29 cells (type A1 and A2), marked shrinkage occurred; the cellular shape became almost completely round with a smooth surface and the beating ceased 3.0 +/- 0.4 hours later. Then, smooth budding appeared 0.6 +/- 0.2 hours later. Apoptotic bodies were found in 8 cells 10 +/- 4 hours later (type A1, 13%) but not in 21 cells (type A2, 35%). In the other 7 cells (type A3, 12%), the cell surface became rough 8 +/- 3 hours later and the beating ceased. Maximal beating rate was greatest in type A1 (72 +/- 26/min) and greater in type A2 (29 +/- 5/min) than in type A3 (10 +/- 2/min). Electron microscopy confirmed apoptotic ultrastructure even in the cardiomyocytes with bone-, club-like, or square shapes, suggesting that type A3 as well as A1 and A2 is also under apoptotic process. A caspase inhibitor, zVAD.fmk, blocked beating, apoptotic morphology, and DNA fragmentation, indicating these depended on caspase activation. In the caspase-dependent apoptotic process of cultured adult cardiomyocytes, beating and the following deformity of the cellular edges were the initial signs and the rate of beating was related with the subsequent three different processes of apoptosis.

In chronic obstructive pulmonary disease (COPD) which consists of emphysema and chronic bronchitis, alveolar tissue and/or bronchiolar walls are progressively destroyed. This suggests cell death by necrosis and/or apoptosis although no direct evidence of apoptosis has been reported. It was speculated that the apoptosis-related factors are associated with the progression of COPD. Fas/Apo-1 receptor (Fas), Fas ligand (Fas-L) and soluble Fas ligand (sFas-L) are inducers, while soluble Fas (sFas) is an inhibitor of apoptosis. In this study, plasma sFas and sFas-L were measured in 19 COPD patients receiving supplemental O2 (severe COPD) and 20 COPD patients not receiving supplemental O2 (mild/moderate COPD). Twenty-two age- and sex-matched healthy volunteers (healthy controls) and 20 patients receiving supplemental O2 and with level of hypoxaemia similar to severe COPD due to other pulmonary diseases (disease controls) were also examined. Plasma sFas-L was within normal limits in all groups. Plasma sFas levels were similar among healthy controls, disease controls, and mild/moderate COPD patients, but significantly increased in severe COPD (2.6 +/- 1.1, 2.6 +/- 0.2, 2.8 +/- 0.2 and 4.8 +/- 1.0 ng ml-1, respectively). Although PaO2 was lower in severe COPD than in mild/moderate COPD, and PaCO2 was higher in severe COPD than in mild/moderate COPD, they were close between severe COPD and disease controls. Tumour necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6) and C-reactive protein (CRP) were increased in patients with COPD, but were similar in both severe and mild/moderate COPD patients. We conclude that increased plasma sFas, which is independent of hypoxaemia, and increases in PaCO2, TNF-alpha, IL-6 and inflammation, may be associated with progression of COPD.

Unlabelled: We examined whether nicorandil reduces myocardial infarct size (1) when administered before ischemia, and (2) when administered before reperfusion, and whether (3) infarct size is influenced by the plasma nicorandil concentration and the opening of the K(ATP) channel. Anesthetized open-chest Japanese white male rabbits were subjected to a 30 min coronary occlusion (ischemia) and a 48 h reperfusion in the following six groups; Group 1 (n=9): control group, Group 2 (n=9): pre-ischemia to post-reperfusion group (nicorandil 10 microg/kg/min, i.v.), Group 3 (n=7): pre-ischemia to post-reperfusion+glibenclamide group (glibenclamide 0.3 microg/kg, i.v.+nicorandil 10 microg/kg/min, i.v.), Group 4 (n=8): pre-reperfusion to post-reperfusion group (nicorandil 10 microg/kg/min, i.v.), Group 5 (n=8): pre-ischemia low-dose group (nicorandil 10 microg/kg/min for 5 min i.v.), Group 6 (n=7): pre-ischemia high-dose group (nicorandil 100 microg/kg/min for 5 min i.v.). The plasma nicorandil concentrations were measured from blood samples taken immediately before the ischemia. After the 48 h reperfusion, the size of the infarct was measured histologically with immunohistochemical actin staining and expressed as a percentage of the area at risk., Results: Infarct sizes were as follows; Group 1 (control): 41.0+/-3.5%, Group 2: 31.3+/-2.0% (P<0.05 vs. control), Group 3: 40.9+/-3.4%, Group 4: 45.2+/-4.4%, Group 5: 35.8+/-3.3%, Group 6: 25.2+/-3.9% (P<0.05 vs. control). Infarct size was inversely correlated with the plasma nicorandil concentrations (y=-0.031x+41.0, r=0.65, P<0.05)., Conclusions: The pre-ischemic but not post-ischemic administration of nicorandil reduced the size of myocardial infarct by opening the K(ATP) channels, and this effect was dependent on the plasma nicorandil concentrations immediately before the ischemia induced in rabbits.