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Arterial stiffness contributes to the development of cardiovascular disease (CVD). However, the relationship between the arterial stiffness and exercise tolerance in CVD patients with preserved ejection fraction (pEF) and those with reduced EF (rEF) is unclear. We enrolled 358 patients who participated in cardiac rehabilitation and underwent cardiopulmonary exercise testing at Juntendo University Hospital. After excluding 195 patients who had undergone open heart surgery and 20 patients with mid-range EF, the patients were divided into pEF (n = 99) and rEF (n = 44) groups. Arterial stiffness was assessed using arterial velocity pulse index (AVI) and arterial pressure volume index (API) at rest. The patients in the pEF group were significantly older and had a higher prevalence of coronary artery disease than the rEF group. The pEF group had significantly lower AVI levels and higher API levels than the rEF group. In the pEF group, the peak oxygen uptake (peak VO2) and the anaerobic threshold was significantly higher than those in the rEF group. The peak VO2 was significantly and negatively correlated with AVI and API in the pEF group (All, P < 0.05), but not in the rEF group. Multivariate linear regression analyses demonstrated that AVI was independently associated with peak VO2 (β = -0.34, P < 0.05) in the pEF group. In conclusion, AVI may be a useful factor for assessing exercise tolerance, particularly in CVD patients with pEF.

Planarian Dugesia japonica is a flatworm that can autonomously regenerate its own body after an artificial amputation. A recent report showed the role of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) pathway in the head morphogenesis during the planarian regeneration process after amputation; however, neuron-specific regeneration mechanisms have not yet been reported. Here, whether MEK/ERK pathway was involved in the dopaminergic neuronal regeneration in planarians was investigated. Planarians regenerated their body within 14 days after amputation; however, the head region morphogenesis was inhibited by MEK inhibitor U0126 (3 or 10 μM). Furthermore, the number of planarian tyrosine hydroxylase (DjTH)-positive dopaminergic neurons in the regenerated head region was also decreased by U0126. The 6-hydroxydopamine (6-OHDA), a dopaminergic neurotoxin, can decrease the number of dopaminergic neurons; however, planarians can regenerate dopaminergic neurons after injecting 6-OHDA into the intestinal tract. MEK inhibitor PD98059 (30 μM) or U0126 (10 μM) significantly decreased dopaminergic neurons 5 days after the 6-OHDA injection. During the regeneration process of dopaminergic neurons, phosphorylated histone H3 (H3P)-positive stem cells known as “neoblasts” were increased in the head region; however, MEK inhibitors significantly decreased the number of H3P-positive neoblasts. These results suggested that dopaminergic neuronal regeneration in planarian was regulated by the MEK/ERK pathway.

We investigated the effects of voluntary exercise after myocardial infarction (MI) on cardiac function, remodeling, and inflammation. Male C57BL/6J mice were divided into the following four groups: sedentary + sham (Sed-Sh), sedentary + MI (Sed-MI), exercise + sham (Ex-Sh), and exercise + MI (Ex-MI). MI induction was performed by ligation of the left coronary artery. Exercise consisting of voluntary wheel running started after the operation and continued for 4 weeks. The Ex-MI mice had significantly increased cardiac function compared with the Sed-MI mice. The Ex-MI mice showed significantly reduced expression levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-10 in the infarcted area of the left ventricle compared with the Sed-MI mice. In the Ex-MI mice, the expression levels of fibrosis-related genes including collagen I and III were decreased compared to the Sed-MI mice, and the expression levels of IL-1β, IL-6, follistatin-like 1, fibroblast growth factor 21, and mitochondrial function-related genes were significantly elevated in skeletal muscle compared with the Sed mice. The plasma levels of IL-6 were also significantly elevated in the Ex-MI group compared with the Sed-MI groups. These findings suggest that voluntary exercise after MI may improve in cardiac remodeling associated with anti-inflammatory effects in the myocardium and myokine production in the skeletal muscles.

Aim We examined the changes in oxidative stress, mitochondrial function and muscle atrophy during aging in mice. Methods We used 6-, 12- and 24-month (6 M, 12 M and 24 M)-old C57BL/6J mice. Skeletal muscles were removed from the lower limb and used for quantitative real-time polymerase chain reaction, immunoblotting and histological analyses. Results The muscle weight and myocyte cross-sectional area were significantly decreased in the 12 M and 24 M mice compared with those of the 6 M mice. The levels of the oxidative stress markers, nicotinamide adenine dinucleotide phosphate oxidase 2, nicotinamide adenine dinucleotide phosphate oxidase 4, mitochondrial 4-hydroxy-2-nonenal and 3-nitrotyrosine, were significantly higher in the 24 M mice compared with those of the 6 M mice. Furthermore, the 24 M mice had lower levels of mitochondrial markers, peroxisome proliferator-activated receptor gamma coactivator 1 (PGC)-α, peroxisome proliferator-activated receptor gamma coactivator-1β, sirtuin-1, adenosine triphosphate synthase mitochondria F1 complex α subunit 1 and mitochondrial cytochrome c oxidase 1. The ubiquitin-proteasome pathway genes muscle ring finger-1 and atrogin-1 were significantly upregulated in the 12 M and 24 M mice, and protein synthesis markers (phosphorylated-Akt and -p70 ribosomal S6 kinase) were significantly lower in the 24 M mice compared with the 6 M mice (all P Conclusions These findings have important implications for the mechanisms that underlie sarcopenia and frailty processes. Geriatr Gerontol Int 2020; 20: 78-84.

Background Advanced glycation end-products, indicated by skin autofluorescence (SAF) levels, could be prognostic predictors of all-cause and cardiovascular mortality in patients with diabetes mellitus (DM) and renal disease. However, the clinical usefulness of SAF levels in patients with heart failure (HF) who underwent cardiac rehabilitation (CR) remains unclear. This study aimed to investigate the associations between SAF and MACE risk in patients with HF who underwent CR. Methods This study enrolled 204 consecutive patients with HF who had undergone CR at our university hospital between November 2015 and October 2017. Clinical characteristics and anthropometric data were collected at the beginning of CR. SAF levels were noninvasively measured with an autofluorescence reader. Major adverse cardiovascular event (MACE) was a composite of all-cause mortality and unplanned hospitalization for HF. Follow-up data concerning primary endpoints were collected until November 2017. Results Patients’ mean age was 68.1 years, and 61% were male. Patients were divided into two groups according to the median SAF levels (High and Low SAF groups). Patients in the High SAF group were significantly older, had a higher prevalence of chronic kidney disease, and more frequently had history of coronary artery bypass surgery; however, there were no significant between-group differences in sex, prevalence of DM, left ventricular ejection fraction, and physical function. During a mean follow-up period of 590 days, 18 patients had all-cause mortality and 36 were hospitalized for HF. Kaplan–Meier analysis showed that patients in the high SAF group had a higher incidence of MACE (log-rank P Conclusion SAF levels were significantly associated with the incidence of MACE in patients with HF and may be useful for risk stratification in patients with HF who underwent CR.

Arterial stiffness contributes to the development of cardiovascular disease (CVD). However, the relationship between the arterial stiffness and exercise tolerance in CVD patients with preserved ejection fraction (pEF) and those with reduced EF (rEF) is unclear. We enrolled 358 patients who participated in cardiac rehabilitation and underwent cardiopulmonary exercise testing at Juntendo University Hospital. After excluding 195 patients who had undergone open heart surgery and 20 patients with mid-range EF, the patients were divided into pEF (n = 99) and rEF (n = 44) groups. Arterial stiffness was assessed using arterial velocity pulse index (AVI) and arterial pressure volume index (API) at rest. The patients in the pEF group were significantly older and had a higher prevalence of coronary artery disease than the rEF group. The pEF group had significantly lower AVI levels and higher API levels than the rEF group. In the pEF group, the peak oxygen uptake (peak VO

Background Peak oxygen uptake (peak VO2) and heart rate reserve (HRR) are independent prognostic markers of cardiovascular disease. However, the impact of peak VO2 and HRR on long‐term prognosis after off‐pump coronary artery bypass grafting (OP‐CABG) remains unclear. Hypothesis To determine the prognostic impact of peak VO2 and HRR in patients after OP‐CABG. Results We enrolled 327 patients (mean age, 65.1 ± 9.3 years; male, 80%) who underwent OP‐CABG and participated in early phase II cardiac rehabilitation. All participants underwent cardiopulmonary exercise testing (CPET) at the beginning of such rehabilitation. Overall, 48 (14.6%) patients died during the median follow‐up period of 103 months. The non‐survivor had significantly lower levels of peak VO2 (10.6 ± 0.5 vs. 13.7 ± 0.2 ml/kg/min, p

Planarian Dugesia japonica is a flatworm that can autonomously regenerate its own body after an artificial amputation. A recent report showed the role of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) pathway in the head morphogenesis during the planarian regeneration process after amputation; however, neuron-specific regeneration mechanisms have not yet been reported. Here, whether MEK/ERK pathway was involved in the dopaminergic neuronal regeneration in planarians was investigated. Planarians regenerated their body within 14 days after amputation; however, the head region morphogenesis was inhibited by MEK inhibitor U0126 (3 or 10 μM). Furthermore, the number of planarian tyrosine hydroxylase (DjTH)-positive dopaminergic neurons in the regenerated head region was also decreased by U0126. The 6-hydroxydopamine (6-OHDA), a dopaminergic neurotoxin, can decrease the number of dopaminergic neurons; however, planarians can regenerate dopaminergic neurons after injecting 6-OHDA into the intestinal tract. MEK inhibitor PD98059 (30 μM) or U0126 (10 μM) significantly decreased dopaminergic neurons 5 days after the 6-OHDA injection. During the regeneration process of dopaminergic neurons, phosphorylated histone H3 (H3P)-positive stem cells known as "neoblasts" were increased in the head region; however, MEK inhibitors significantly decreased the number of H3P-positive neoblasts. These results suggested that dopaminergic neuronal regeneration in planarian was regulated by the MEK/ERK pathway.

Background Advanced glycation end products (AGEs) are associated with aging, diabetes mellitus (DM), and other chronic diseases. Recently, the accumulation of AGEs can be evaluated by skin autofluorescence (SAF). However, the relationship between SAF levels and exercise capacity in patients with cardiovascular disease (CVD) remains unclear. This study aimed to investigate the association between the tissue accumulation of AGEs and clinical characteristics, including exercise capacity, in patients with CVD. Methods We enrolled 319 consecutive CVD patients aged ≥40 years who underwent early phase II cardiac rehabilitation (CR) at our university hospital between November 2015 and September 2017. Patient background, clinical data, and the accumulation of AGEs assessed by SAF were recorded at the beginning of CR. Characteristics were compared between two patient groups divided according to the median SAF level (High SAF and Low SAF). Results The High SAF group was significantly older and exhibited a higher prevalence of DM than the Low SAF group. The sex ratio did not differ between the two groups. AGE levels showed significant negative correlations with peak oxygen uptake and ventilator efficiency (both P P P = 0.02). Conclusion High levels of tissue accumulated AGEs, as assessed by SAF, were significantly and independently associated with reduced exercise capacity. These data suggest that measuring the tissue accumulation of AGEs may be useful in patients who have undergone CR, irrespective of whether they have DM.

Background Left ventricular (LV) remodeling, through excessive inflammation, leads to heart failure. Exercise (Ex) training is associated with a risk reduction in heart failure through direct and indirect mechanisms by which Ex contributes an anti-inflammatory effect. During Ex, contracting muscle fibers release myokines, including interleukins (ILs), tumor necrosis factor α (TNF-α), follistatin-like protein 1 (FSTL-1), and fibroblast growth factor 21 (FGF-21), into the bloodstream. These myokines may have beneficial effects on other damaged organs, such as an infarcted myocardium, through anti-inflammatory effects. However, the exact mechanisms of the anti-inflammatory effects of voluntary Ex in myocardial infarction (MI) are poorly understood. Therefore, we investigated the effect of voluntary Ex on cardiac remodeling and inflammation, the relationship between cardiac remodeling and skeletal muscle (SKM) response, and circulating myokine levels in a mouse model of MI. Methods Twelve-week-old male C57BL/6J mice were used and divided into the following 4 groups: sham operation (Sham), MI, Sham+Ex, and MI+Ex. MI was induced by ligation of the left anterior descending coronary artery. Ex groups began voluntary wheel running for 4 weeks after the operation. An echocardiography was performed at baseline and 4 weeks after the operation. The mRNA levels in the LV infarcted area and SKM were measured with RT-PCR and western blot analysis. Plasma levels of myokines were also measured with immunoassays. Results Four weeks after MI induction, echocardiographic evaluation showed that the MI mice had a larger LV end-diastolic diameter (LVEDD) and end-systolic diameter (LVESD) than the Sham mice. The MI mice also showed higher mRNA levels of TNF-α, IL-1β, IL-6, and IL-10 in the LV tissue when compared to the Sham mice. These changes were significantly ameliorated in the MI+Ex mice. Interestingly, in the MI+Ex mice, mRNA levels of IL-6, IL-1β, FSTL-1, and FGF-21 in the SKM were significantly higher than in the MI mice, while there were no significant differences in TNF-α and IL-10 levels in all groups. Similarly, protein expression levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, sirtuin-1, and mitochondrial transcriptional factor A of mitochondrial function markers in SKM were also significantly higher in the MI+Ex mice than in the MI mice. Furthermore, there were significant correlations between plasma levels of IL-1β, but not other myokines, and LVEDD, and LVESD. In addition, there was also a significant correlation between the SKM IL-1β level and LVESD in the Sham+Ex mice (all, P Conclusions Amelioration of cardiac remodeling and inflammation by voluntary Ex is associated with increased myokines, especially IL-1β, in a MI mouse model. These results suggest that increased myokine levels, through voluntary exercise, may play an important role in the prevention of cardiac remodeling after MI.

Background Advanced glycation end-products, indicated by skin autofluorescence (SAF) levels, could be prognostic predictors of all-cause and cardiovascular mortality in patients with diabetes mellitus (DM) and renal disease. However, the clinical usefulness of SAF levels in patients with heart failure (HF) who underwent cardiac rehabilitation (CR) remains unclear. Purpose The purpose of this study was to investigate the prognostic value of SAF levels in patients with HF who underwent CR. Methods This study enrolled 204 consecutive patients with HF who had undergone CR at our university hospital between November 2015 and October 2017. Clinical characteristics and anthropometric data were collected at the beginning of CR. SAF levels were noninvasively measured with an autofluorescence reader. The major adverse cardiovascular event (MACE) was a composite of all-cause mortality and unplanned hospitalization for HF. Follow-up data concerning primary endpoints were collected until November 2018. Results Patients' mean age was 68.1 years, and 61% were males. Patients were divided into two groups according to the median SAF levels (high and low SAF groups). Patients in the high SAF group were significantly older, had a higher prevalence of chronic kidney disease, and histories of coronary artery bypass surgery; however, there were no significant between-group differences in sex, prevalence of DM, left ventricular ejection fraction, and physical function. During a median follow-up period of 623 days, 25 patients experienced all-cause mortality and 34 were hospitalized for HF. Kaplan–Meier analysis showed that patients in the high SAF group had a higher incidence of MACE (log-rank P Figure 1 Conclusion SAF levels were significantly associated with the incidence of MACE in patients with HF and may be useful for risk stratification in patients with HF who undergo CR.

Key Clinical Message Polycythemia vera (PV) is a chronic myeloproliferative disease that is often complicated with thromboembolism. However, aortic stenosis (AS) could be a manifestation of the cardiovascular complications of PV possibly through shear stress and atherosclerosis. We report a rare case of rapidly progressed AS in a patient with PV.

AIM The Kihon Checklist is a useful screening tool for assessing frailty in older individuals. However, the clinical significance of the Kihon Checklist in cardiac rehabilitation patients remains unclear. The present study aimed to evaluate the relationship between the Kihon Checklist and the clinical parameters in patients who participated in cardiac rehabilitation. METHODS We enrolled 845 consecutive patients (584 men, mean age 71 years) who participated in cardiac rehabilitation at Juntendo University Hospital, Tokyo, Japan, between November 2015 and October 2017. The patients were divided into non-frailty (n = 287), pre-frailty (n = 270) and frailty (n = 288) groups according to their Kihon Checklist scores. Cardiopulmonary exercise testing was carried out in 302 patients. RESULTS The frailty group was older and had a higher prevalence of history of heart failure than the non-frailty group, although left ventricular ejection fraction did not differ significantly between groups. Nutritional index, trunk and limb muscle mass, lean body weight, and grip strength were significantly lower in the frailty and pre-frailty groups than those in the non-frailty group. In the cardiopulmonary exercise test, a stepwise significant decrease in peak oxygen uptake was observed across the three groups (non-frailty 17.2 ± 3.6, pre-frailty 16.0 ± 3.4, frailty 14.4 ± 3.5 mL/kg/min, P

Background and objectives: Exercise can help ease withdrawal symptoms of smokers. However, there is little information about the physiological responses, such as cardiorespiratory and lactate (La) responses, during exercise from light to moderate intensity combined with transdermal nicotine patches (TNPs) in smokers. This study aimed to investigate the effect of TNPs on the cardiorespiratory and La responses during exercise at light to moderate intensity. Materials and Methods: Fourteen young men (8 non-smokers, 6 current smokers) aged 20 to 26 years participated in this study. They performed an incremental graded submaximal exercise test using an electromagnetic cycle ergometer set from 30 to 210 W with (TNP condition) or without a TNP (control condition) in a random order. The TNP was applied to the left arm 8&ndash, 10 h prior to starting the exercise to achieve the peak level of blood nicotine concentration. Heart rate (HR), rate of perceived exertion (RPE), oxygen consumption (VO2), ventilation (VE), and blood La at rest and during exercise were measured and analyzed. Results: The HR at rest was significantly higher in the TNP condition than in the control condition (TNP, 74.7 &plusmn, 13.8 bpm, control, 65.3 &plusmn, 10.8 bpm, p &lt, 0.001). There was no interaction (condition &times, exercise intensity) between any of the variables, and VO2, VE, RPE, and La during exercise were not significantly different between the conditions. However, HR during exercise was 6.7 bpm higher on average in the TNP condition. Conclusions: The HR during exercise was greater at light to moderate intensity with a TNP. Our study results will guide clinicians or health professionals when prescribing exercise programs combined with TNPs for healthy young smokers.

Background The effects of cardiac rehabilitation (CR) on muscle mass, muscle strength, and exercise tolerance in patients with diabetes mellitus (DM) who received CR after coronary artery bypass grafting (CABG) have not been fully elucidated. Methods We enrolled 78 consecutive patients who completed a supervised CR for 6 months after CABG (DM group, n = 37; non-DM group, n = 41). We measured mid-upper arm muscle area (MAMA), handgrip power (HGP), muscle strength of the knee extensor (Ext) and flexor (Flex), and exercise tolerance at the beginning and end of CR. Results No significant differences in confounding factors, including age, gender, ejection fraction, or number of CR sessions, were observed between the two groups. At the beginning of CR, the levels of Ext muscle strength and peak VO2 were significantly lower in the DM group than in the non-DM group. At the end of CR, significant improvement in the levels of muscle strength, HGP, and exercise tolerance was observed in both groups. However, the levels of Ext muscle strength, HGP, peak VO2, thigh circumference, and MAMA were significantly lower in the DM group than in the non-DM group. In addition, no significant improvement in thigh circumference and MAMA was observed in the DM group. At the end of CR, the levels of thigh circumference and MAMA correlated with Ext and Flex muscle strength as well as with HGP. Percent changes in the levels of Ext muscle strength were significantly correlated with those of MAMA and hemoglobin A1c. Conclusions These data suggest that improvement in muscle strength may be influenced by changes in muscle mass and high glucose levels in DM patients undergoing CR after CABG. A CR program, including muscle mass intervention and blood glucose control, may improve deterioration in exercise tolerance in DM patients after CABG.

Aim Very long chain saturated fatty acid (VLCFA) levels in erythrocytes are associated with metabolic syndrome (MS). However, the relationship between levels of the VLCFA ligonoceric acid (C24:0) in erythrocytes and the atherogenic lipoprotein profiles and inflammatory state in MS remain unclear. Methods Based on the International Diabetes Federation (IDF) definition of MS, 195 apparently healthy males were assigned to either an MS group (n = 38) or a non-MS group (n = 157). Fatty acid composition of erythrocytes was determined by gas liquid chromatography. Results Erythrocytes from the MS group had a significantly higher level of C24:0 than cells from the non-MS group (4.06 ± 0.48% versus 3.88 ± 0.34%; p = 0.03). C24:0 levels were significantly correlated with several components of MS. The C24:0 levels showed a significant negative correlation with LDL and HDL particle size. Multivariate linear regression analysis showed that C24:0 levels were independently correlated with LDL particle size after adjusting for age and each MS criterion. C24:0 levels were also positively correlated with log-transformed high-sensitivity CRP levels (p = 0.04). Conclusion C24:0 levels in erythrocytes are associated with specific atherogenic lipoprotein profiles and inflammation status in subjects with MS.

Biological response of exposure to radon progeny has long been investigated, but there are only few studies in which absorbed doses in lungs of laboratory animals were estimated. The present study is the first attempt to calculate the doses of inhaled radon progeny for mice. For reference, the doses for rats and humans were also computed with the corresponding models. Lung deposition of particles, their clearance, and energy deposition of alpha particles to sensitive tissues were systematically simulated. Absorbed doses to trachea and bronchi, bronchioles and terminal bronchioles, alveolar-interstitial regions, and whole lung were first provided as a function of monodisperse radon progeny particles with an equilibrium equivalent radon concentration of 1 Bq m(-3) (equilibrium factor, 0.4 and unattached fraction, 0.01). Based on the results, absorbed doses were then calculated for (1) a reference mine condition and (2) a condition previously used for animal experiments. It was found that the whole lung doses for mice, rats, and humans were 34.8, 20.7, and 10.7 nGy (Bq m(-3))(-1) h(-1) for the mine condition, respectively, while they were 16.9, 9.9, and 6.5 nGy (Bq m(-3))(-1) h(-1) for the animal experimental condition. In both cases, the values for mice are about 2 times higher than those for rats, and about 3 times higher than those for humans. Comparison of our data on rats and humans with those published in the literature shows an acceptable agreement, suggesting the validity of the present modeling for mice. In the future, a more sophisticated dosimetric study of inhaled radon progeny in mice would be desirable to demonstrate how anatomical, physiological, and environmental parameters can influence absorbed doses.

Background: Acute coronary syndrome (ACS) is an amplified state of inflammation and immune reaction. Dendritic cells (DCs) expressing various Toll-like receptors (TLRs) have been observed in atherosclerotic lesions, however, the clinical significance of DCs in pathogenesis of ACS has not been completely investigated. Methods: Ten patients with ACS and 10 patients with stable angina pectoris (SAP) were enrolled in this study. Monocyte-derived DCs were generated from CD14+ cells by culturing with granulocyte macrophage colony-stimulating factor and interleukin (IL)-4 for 6 days. Expression of cell surface CD86 and CD83 were measured by flowcytometry. Expression of genes, including CD86, CD83, CCL19, CCR7, TLR2, TLR4, TLR5, TLR8, and TLR9, were measured by real-time PCR. Plasma IL-6 and tumor necrosis factor (TNF)-α levels were also measured. Results: The number of CD86+CD83+DCs in the ACS group was significantly higher than that in the SAP group (P P P +CD83+ cells and plasma levels of IL-6 (P = 0.88, P +CD83+ cells TNF-α levels (r = 0.78, P < 0.0001). Conclusions: These results demonstrated that mono-cyte-derived DCs are activated in patients with ACS, suggesting that activated DCs may play an important role in the pathogenesis of ACS.

Background: Patients with arteriosclerosis obliterans (ASO) often have co-existing atherosclerotic diseases. The purpose of this study was to examine the clinical features of patients with ASO, including the overlap of atherosclerotic risk factors, characteristics of car-diovascular events, and clinical prognosis. Method: We enrolled 205 consecutive patients who had ankle brachial index (ABI) of ?0.9 between January 2008 and December 2009. Fontaine (F) classification and clinical background were evaluated and clinical events including mortality and major adverse cardiocerebro-vascular events (MACCEs) were determined. Results: There was a high prevalence of each risk factor. Sixty- five percent of subjects had three or more of the four overlapping risk factors, including hypertension, dia- betes, dyslipidemia, and smoking. After a maximum follow-up of 800 days, the incidence of MACCEs and mortality was 46% and 10%, respectively. We divided the patients into two groups according to the presence of ASO symptoms (F1 and F2-4) and compared the incidence of events. The incidence of MACCEs and mortality in the F2-4 group was significantly higher than that in the F1 group (P = 0.048, P = 0.044, respectively). After excluding lower extremity revascularization, coronary artery disease was a common cause of MACCEs, and the mortality rates after MACCEs increased in a stepwise manner according to F classification severity (P = 0.028). Conclusion: Patients with ASO had overlapping coronary risk factors and a high incidence rate of cardiovascular events. The incidence of coronary events was common, especially in symptomatic patients, and the mortality rates after MACCEs were high in accordance with F classification severity.

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a diagnostic biomarker for patients with congestive heart failure (CHF). However, the clinical significance of measurements of NT-proBNP levels in patients with coronary artery disease (CAD) who have undergone drug-eluting stent (DES) implantation has not been fully elucidated.We recruited 280 patients with documented CAD who were scheduled for elective coronary intervention and also age- and gender-matched 140 healthy subjects. Subjects with acute coronary syndrome, ongoing CHF, and stage IV or V chronic kidney disease were excluded. We measured the plasma NT-proBNP levels and followed the CAD patients who have undergone DES implantation for up to 62 months until occurrence of major adverse cardiovascular events (MACE). Plasma NT-proBNP levels were significantly higher in CAD patients compared to control subjects (p0.0001). In the CAD group, 25 patients developed MACE and the NT-proBNP levels in the MACE group were significantly higher compared to that in the non-MACE group (p=0.005). After adjusting for the confounding factors, high NT-proBNP levels were observed to be independent factors for CAD (p0.0001) and MACE (p=0.021).These results demonstrated that the measurements of NT-proBNP levels may be useful in identifying high-risk subjects among CAD patients who have undergone elective DES implantation.

Aim: We assessed levels of polyunsaturated fatty acid (PUFA) in serum and red blood cells (RBCs) among groups stratified by generation and its clinical significance in Japanese subjects living in an urban area.Methods: We enrolled 200 apparently healthy Japanese (126 males, mean age: 50.3±9.2 years) living in an urban area. Levels of PUFA, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and dihomo-gamma-linolenic acid (DGLA) in serum and RBCs were measured for each generation (G1

Background: Post-prandial hyperglycemia, hyperlipidemia, and endothelial dysfunction play an important role in the pathogenesis of atherosclerosis. Improvement in post-prandial hyperglycemia on α-glucosidase inhibitors (α-GIs) is associated with a risk reduction of cardiovascular diseases, but the post-prandial effects of α-GIs on endothelial function and incretin secretion in type 2 diabetic patients with coronary artery disease (CAD) remain unclear. Methods and Results: The post-prandial effects of a single administration of miglitol and voglibose on endothelial function and changing levels of glucose, insulin, lipids, glucagon-like peptide (GLP)-1, and gastric inhibitory polypeptide (GIP) were compared after a standard meal loading in 11 diabetic patients with CAD, using a placebo-controlled cross-over design. The changing levels of glucose, insulin and triglycerides at 60 min were significantly lower in the miglitol group than in the voglibose and placebo groups (all P

Aim: A sedentary lifestyle with insufficient exercise is associated with cardiovascular disease. Previous studies have demonstrated that endurance exercise benefits atherosclerosis and cardiovascular disorders; however, the mechanisms by which physical activity, such as voluntary exercise (Ex), produces these effects are not fully understood.Methods and Results: Eight-week-old male apolipoprotein (ApoE)-deficient mice were fed a standard diet (STD) or high fat diet (HFD) for 10 weeks. The HFD+Ex group mice performed Ex on a running wheel for 10 weeks. No significant differences in lipid profiles were observed between the HFD and HFD+Ex groups. Although changes in body and brown adipose tissue weights were comparable between the HFD and HFD+Ex groups, white adipose tissue weight was significantly lower in the HFD+Ex group than in the HFD group. The areas of atherosclerotic lesions in the aortic sinus and thoracoabdominal aorta were significantly reduced in the HFD+Ex group than in the HFD group (p

Background: Cardiac rehabilitation (CR) has numerous benefits, including reduction of mortality and cardiovascular events, in patients with coronary artery disease (CAD). However, the long-term effect of phase III CR in elderly patients with stable CAD is still unknown. Methods and Results: The 111 elderly male CAD patients (≥65 years), including 37 subjects participating in supervised CR for 6 months and 74 age-matched controls, were analyzed. The patients were followed for up to 3,500 days, until the occurrence of death or 1 of the following major adverse cardiovascular events (MACE): cardiovascular death, acute coronary syndrome, refractory angina requiring revascularization, admission for congestive heart failure, or stroke. All-cause mortality tended to be lower in the CR group than in the Control group (14% vs 28%, P=0.081). The MACE incidence was significantly lower in the CR group than in the Control group (30% vs 62%, P=0.001). Multivariate Cox proportional hazard analysis showed that the MACE incidence was significantly lower in the CR group than in the Control group [adjusted hazard ratio 0.43 (95% confidence interval 0.20-0.91), P=0.027]. Conclusions: Phase III CR has the beneficial effect of reducing cardiovascular events even in elderly patients with stable CAD. (Circ J 2010; 74: 709-714)

Background Dietary intake of ω3 polyunsaturated fatty acids (ω3-PUFAs) reduces progression of atherosclerosis and prevents future cardiovascular events. Macrophages are key players in the pathogenesis of aortic aneurysm. The effects of ω3-PUFAs on abdominal aortic aneurysm (AAA) formation and macrophage-mediated inflammation remain unclear. METHODS AND RESULTS: The AAA model was developed by angiotensin II infusion in apolipoprotein E-deficient mice. Mice were supplemented with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA). The development of AAA lesions and macrophage infiltration in the aorta were analyzed. Gene expression of inflammatory markers in aortic tissues and peritoneal macrophages were measured by using quantitative polymerase chain reaction. AAA formation and macrophage infiltration were significantly suppressed after EPA and DHA administration. EPA administration and DHA administration significantly decreased the expression of tumor necrosis factor-α, monocyte chemoattractant protein-1, transforming growth factor-β, matrix metalloproteinases (MMP)-2, MMP-9, and vascular cell adhesion molecule-1 in the aortas. The expression of arginase 2, which is a marker of pro-inflammatory macrophages, was significantly lower and that of Ym1, which is a marker of anti-inflammatory macrophages, and was significantly higher after EPA and DHA administration. The same trends were observed in peritoneal macrophages after EPA and DHA administration. Conclusions Dietary intake of EPA and DHA prevented AAA development through the inhibition of aortic and macrophage-mediated inflammation.

BackgroundRecently, much attention has been focused on cardio-renal interaction. Urinary liver-type fatty acid binding protein (U-L-FABP), which is produced in the proximal tubule by renal hypoxia and oxidative stress, has been identified as a useful marker for diagnosis of acute kidney disease and a predictor of future events in chronic kidney disease. However, the clinical significance of U-L-FABP measurements in patients with acute coronary syndrome (ACS) has not been completely evaluated.Methods and resultsThis study included 50 consecutive patients with ACS [37 with acute myocardial infarction (AMI) and 13 with unstable angina pectoris (UAP)] and 47 subjects without coronary artery disease (control group). U-L-FABP levels, urinary albumin (U-Alb), and other serum parameters were measured at admission and at 24h after percutaneous coronary intervention.ResultsU-L-FABP levels in patients with AMI were significantly higher (p=0.0019), than in control subjects, while patients with UAP did not exhibit such an increase. U-L-FABP levels at admission were positively correlated with brain natriuretic protein levels (p=0.001) and duration of hospitalization (p=0.025). At follow-up angiography, patients with restenosis had significantly higher U-L-FABP (p=0.047) and U-Alb levels (p

Background Hypertension is associated with impaired glucose tolerance and insulin resistance. Medical treatment that interferes with various steps in the renin-angiotensin system improves glucose tolerance and insulin resistance. However, it remains unclear if long-acting calcium channel blockers (CCBs) such as azelnidipine and amlodipine affect glucose tolerance and insulin resistance in clinical practice. Methods Seventeen non-diabetic patients with essential hypertension who had controlled blood pressure levels using amlodipine (5 mg/day) were enrolled in this study. After randomization, either azelnidipine (16 mg/day) or amlodipine (5 mg/day) was administered in a crossover design for 12-weeks. At baseline and the end of each CCB therapy, samples of blood and urine were collected and 75 g oral glucose tolerance test (OGTT) was performed. In addition, hematopoietic progenitor cells (HPCs) were measured at each point by flow cytometry and endothelial functions were measured by fingertip pulse amplitude tonometry using EndoPAT. Results Although blood pressure levels were identical after each CCB treatment, the heart rate significantly decreased after azelnidipine administration than that after amlodipine administration (P < 0.005). Compared with amlodipine administration, azelnidipine significantly decreased levels of glucose and insulin 120 min after the 75 g OGTT (both P < 0.05). Serum levels of high-sensitivity C-reactive protein (P = 0.067) and interleukin-6 (P = 0.035) were decreased. Although endothelial functions were not different between the two medication groups, the number of circulating HPCs was significantly increased after azelnidipine administration (P = 0.016). Conclusions These results suggest that azelnidipine treatment may have beneficial effects on glucose tolerance, insulin sensitivity, the inflammatory state, and number of circulating progenitor cells in non-diabetic patients with essential hypertension.

SummaryBackgroundThe impact of diabetes mellitus (DM) on muscle mass, muscle strength, and exercise tolerance in patients who had undergone coronary artery bypass grafting (CABG) has not been fully elucidated.MethodsWe enrolled 329 consecutive patients who received cardiac rehabilitation (CR) after CABG (DM group, n=178; non-DM group, n=151) and measured lean body weight, mid-upper arm muscle area (MAMA), and handgrip power (HGP) at the beginning of CR. We also performed an isokinetic strength test of the knee extensor (Ext) and flexor (Flex) muscles and a cardiopulmonary exercise testing at the same time.ResultsNo significant differences in risk factors, including age, gender, number of diseased vessels, or ejection fraction were observed between the 2 groups. The levels of Ext muscle strength, peak oxygen uptake, and anaerobic threshold were significantly lower in the DM group than in the non-DM group (all p

Post-prandial hyperglycemia, hyperlipidemia, and endothelial dysfunction play an important role in the pathogenesis of atherosclerosis. Improvement in post-prandial hyperglycemia on alpha-glucosidase inhibitors (alpha-GIs) is associated with a risk reduction of cardiovascular diseases, but the post-prandial effects of alpha-GIs on endothelial function and incretin secretion in type 2 diabetic patients with coronary artery disease (CAD) remain unclear.The post-prandial effects of a single administration of miglitol and voglibose on endothelial function and changing levels of glucose, insulin, lipids, glucagon-like peptide (GLP)-1, and gastric inhibitory polypeptide (GIP) were compared after a standard meal loading in 11 diabetic patients with CAD, using a placebo-controlled cross-over design. The changing levels of glucose, insulin and triglycerides at 60 min were significantly lower in the miglitol group than in the voglibose and placebo groups (all P0.01). GLP-1 levels were significantly higher at 120 min (P0.05) and GIP levels were significantly lower at 30 min and 60 min (P0.05) in the miglitol group compared to other treatments. The reactive hyperemia duration at 120 min was significantly maintained in the miglitol group compared to the other groups.A single administration of miglitol significantly improved post-prandial glucose/lipid metabolism, incretin secretion, and endothelial dysfunction in diabetic patients with CAD, suggesting that miglitol may be a useful anti-atherogenic agent (UMIN000002264).

SummaryBackground and purposePrevious studies have demonstrated that cardiac rehabilitation (CR) improves exercise tolerance and muscle strength in patients with myocardial infarction (MI) and in patients after cardiac surgery. However, the association between exercise tolerance and muscular strength following CR and the comparison of relationships among various disease categories has not been fully examined. The purpose of the present study was to assess the relationship between exercise tolerance and muscle strength following CR in patients after cardiac surgery and patients with MI.Methods and resultsOne hundred and four patients who participated in CR for 6 months were enrolled [post-cardiac valve surgery (VALVE), n=28; post-coronary artery bypass grafting (CABG), n=42; post-acute MI, n=34]. The exercise tolerance, thigh/calf circumferences, and muscle strength were measured before and after CR. At the baseline, the thigh circumference was significantly smaller in the VALVE group than in the MI group. There were significant positive correlations between peak V˙⁡O2 and muscle torques of the lower muscles in all groups. After 6 months, peak V˙⁡O2 and muscle torque were significantly increased in all groups (p

Background : Vascular endothelial dysfunction through the production of reactive oxygen species (ROS) plays an important role in the initiation and progression of atherosclerosis. Immunoglobulin Fc receptor (FcR) involves the activation of immune and inflammatory reaction, however, the role of FcR in endothelial function, ROS production, and atherogenesis, has not clearly elucidated. To examine the hypothesis that FcR deletion blunts the progression of atherosclerotic lesions via improvements of superoxide production and endothelial dysfunction, we generated FcR/LDL receptor double-knockout (DKO) mice. Methods : Mice (8 weeks) with LDL receptor knockout (LDLR-KO) and DKO were fed a high cholesterol diet for 10 weeks. We examined the endothelium-dependent relaxation of isolated thoracic aorta, superoxide production by dihydroethidium-derived fluorescence (DHE) staining before and after high cholesterol feeding. We also assessed atherosclerotic lesions by Oil Red O-staining, macrophage infiltration, and p22phox expression by immnohistochemical analysis. Results : Vascular endothelial-dependent relaxation induced by high cholesterol diet was significantly higher in DKO mice than in LDLR-KO mice (−53 ± 7% vs −22 ± 9, p < 0.05). Superoxide production was significantly lower in DKO mice than in LDLR-KO mice (13.6 ± 10 vs 38.8 ± 20 ×10 3 μ m 2 p < 0.05). The expression of p22phox in DKO mice was significantly lower than in LDLR-KO mice (90 ± 19 vs 141 ± 42 × 10 3 μm 2 p < 0.05). The area of macrophage infiltration of the vascular wall was significantly lower in DKO mice than LDLR-KO mice (34 ± 5 vs 59 ± 17 × 10 3 μ m 2 p < 0.05). The Oil -Red O staining showed the significant reduction of atherosclerotic lesions in DKO mice than in LDLR-KO mice (73 ± 24 vs 133 ± 31 × 10 4 μ m 2 p < 0.005). Conclusion : Deletion of FcR attenuated the production of ROS, vascular inflammation, and endothelial dysfunction, resulting in prevention of atherosclerotic formation in LDLR-KO mice. These data suggested that FcR might be involved in atherosclerotic process through not only vascular inflammation, but also oxidative stress in vasculature.

Summary Background Oxidized low-density lipoprotein (OxLDL) and remnant lipoprotein play a crucial role in the development of atherosclerosis. Recently, a novel method for measuring remnant cholesterol levels (remnant lipoproteins cholesterol homogenous assay: RemL-C) has been established. However, the correlation between OxLDL and remnant lipoprotein , including RemL-C, has not been fully investigated. Methods We enrolled 25 consecutive patients with documented coronary artery disease (CAD) and 20 controls. Remnant-like particle cholesterol (RLP-C) and RemL-C were used to determine the levels of remnant lipoprotein cholesterol. Serum levels of malondialdehyde-modified LDL (MDA-LDL) and OxLDL using a monoclonal antibody DLH3 (OxPC) were used to measure the concentration of circulating OxLDL. Results The CAD group had high levels of fasting glucose and glycosylated hemoglobin (HbA1c), and low levels of high-density lipoprotein cholesterol compared with the control group. Serum levels of total cholesterol or LDL cholesterol were not significantly different between the two groups. The levels of RemL-C ( p = 0.035), MDA-LDL ( p = 0.018), and MDA-LDL/LDL-C ( p = 0.036) in the CAD group were significantly higher than those in the control group. The levels of RLP-C tended to be higher in the CAD group than those in the control group ( p = 0.096). Positive correlations were demonstrated between remnant lipoprotein cholesterol and OxLDL (RLP-C and MDA-LDL/LDL-C, r = 0.45, p = 0.0024, RLP-C and OxPC, r = 0.51, p = 0.0005, RemL-C and MDA-LDL/LDL-C, r = 0.42, p = 0.0044, RemL-C and OxPC, r = 0.43, p = 0.0043). Similar trends were observed in non-diabetic subjects and in subjects without metabolic syndrome. Positive correlations were also observed between RLP-C and RemL-C ( r = 0.94, p r = 0.40, p = 0.0074). Conclusions These results suggest that the association between high levels of remnant lipoprotein cholesterol and high OxLDL levels might be linked to atherogenesis in patients with CAD.

Summary Background Cardiac rehabilitation (CR) has numerous beneficial effects, including the modification of coronary risk factors and improvement of the prognosis, in patients with coronary artery disease (CAD). Limited data are available regarding the effects of CR on the physical status and risk factors in patients with metabolic syndrome (MetS) after coronary artery bypass grafting (CABG). Methods and results We enrolled 32 patients with MetS after CABG, who participated in a supervised CR program for 6 months. Metabolic parameters, blood chemistry, exercise tolerance, and muscle strength of the thigh were measured before and after CR. After CR: (1) the body mass index, waist circumference, and fat weight significantly decreased; (2) peak V ˙ O 2 and anaerobic threshold were significantly increased; (3) isokinetic peak torques of knee extensor and flexor muscles significantly increased; (4) metabolic scoring defined by the number of the modified Adult Treatment Panel criteria of the US National Cholesterol Education Program was significantly improved; (5) serum concentration of high-sensitivity C-reactive protein also significantly decreased. Conclusions These results suggest that CR might be useful for patients with MetS after CABG.