Publications by authors named "Masunori Matsuzaki"

258 Publications

Relation of renal function to mid-term prognosis of stable angina patients with high- or low-dose pitavastatin treatment: REAL-CAD substudy.

Am Heart J 2021 10 24;240:89-100. Epub 2021 Jun 24.

Jichi Medical University, Shimotsuke, Japan.

Background: It has not yet been established whether higher-dose statins have beneficial effects on cardiovascular events in patients with stable coronary artery disease (CAD) and renal dysfunction.

Methods: The REAL-CAD study is a prospective, multicenter, open-label trial. As a substudy, we categorized patients by an estimated glomerular filtration rate (eGFR) as follows: eGFR ≥60 (n = 7,768); eGFR ≥45 and <60 (n = 3,176); and eGFR <45 mL/Min/1.73 m (n = 1,164), who were randomized to pitavastatin 4mg or 1mg therapy. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina, and was assessed by the log-rank test and Cox proportional hazards model.

Results: The baseline characteristics and medications were largely well-balanced between two groups. The magnitude of low-density lipoprotein cholesterol (LDL-C) reduction at 6 months in high- and low-dose pitavastatin groups was comparable among all eGFR categories. During a median follow-up of 3.9 years, high- compared with low-dose pitavastatin significantly reduced cardiovascular events in patients with eGFR ≥60 (hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.58-0.91; P = .006), and reduced but not significant for patients with eGFR ≥45 and <60 (HR 0.85; 95% CI, 0.63-1.14; P = .27) or eGFR <45 mL/Min/1.73 m (HR 0.90; 95% CI 0.62-1.33; P = .61). An interaction test of treatment by eGFR category was not significant (P value for interaction = .30).

Conclusion: Higher-dose pitavastatin therapy reduced LDL levels and cardiovascular events in stable CAD patients irrespective of eGFR level, although the effect on events appeared to be numerically lower in patients with lower eGFR.
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http://dx.doi.org/10.1016/j.ahj.2021.06.009DOI Listing
October 2021

High-Density Lipoprotein Cholesterol and Cardiovascular Events in Patients with Stable Coronary Artery Disease Treated with Statins: An Observation from the REAL-CAD Study.

J Atheroscler Thromb 2021 Jan 9. Epub 2021 Jan 9.

Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University.

Aim: The association between high-density lipoprotein cholesterol (HDL-C) level after statin therapy and cardiovascular events in patients with stable coronary artery disease (CAD) remains unclear. Thus, in this study, we sought to determine how HDL-C level after statin therapy is associated with cardiovascular events in stable CAD patients.

Methods: From the REAL-CAD study which had shown the favorable prognostic effect of high-dose pitavastatin in stable CAD patients with low-density lipoprotein cholesterol (LDL-C) <120 mg/dL, 9,221 patients with HDL-C data at baseline and 6 months, no occurrence of primary outcome at 6 months, and reported non-adherence for pitavastatin, were examined. The primary outcome was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina requiring emergent admission after 6 months of randomization. Absolute difference and ratio of HDL-C levels were defined as (those at 6 months-at baseline) and (absolute difference/baseline)×100, respectively.

Results: During a median follow-up period of 4.0 (IQR 3.2-4.7) years, the primary outcome occurred in 417 (4.5%) patients. The adjusted risk of all HDL-C-related variables (baseline value, 6-month value, absolute, and relative changes) for the primary outcome was not significant (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.91-1.08, HR 1.03, 95% CI 0.94-1.12, HR 1.05, 95% CI 0.98-1.12, and HR 1.08, 95% CI 0.94-1.24, respectively). Furthermore, adjusted HRs of all HDL-C-related variables remained non-significant for the primary outcome regardless of on-treatment LDL-C level at 6 months.

Conclusions: After statin therapy with modestly controlled LDL-C, HDL-C level has little prognostic value in patients with stable CAD.
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http://dx.doi.org/10.5551/jat.59881DOI Listing
January 2021

Probucol Trial for Secondary Prevention of Atherosclerotic Events in Patients with Coronary Heart Disease (PROSPECTIVE).

J Atheroscler Thromb 2021 Feb 24;28(2):103-123. Epub 2020 Apr 24.

Sumitomo Hospital.

Aims: Although intensive statin therapy reduced cardiovascular risks, cardiovascular events have not been completely prevented. Probucol is a potent antioxidant and reduces tendon xanthomas in familial hypercholesterolemia patients despite reduction of high-density lipoprotein (HDL)-cholesterol (HDL-C). We investigated whether probucol can reduce cardiovascular events on top of conventional lipid-lowering therapy in patients with coronary heart disease (CHD).

Methods: PROSPECTIVE is a multicenter, randomized, prospective study that recruited 876 Japanese patients with CHD and dyslipidemia with a low-density lipoprotein (LDL)-cholesterol (LDL-C) level of ≥ 140 mg/dL without medication or those treated with lipid-lowering drugs. Lipid-lowering agents were administered during the study period in the control group (n=438), and probucol 500 mg/day was added to lipid-lowering therapy in the probucol group (n=438). Patients were randomly assigned to two treatment groups by adjusting the LDL-C level and presence of diabetes and hypertension and followed up for more than 3 years. The primary end point was a composite of cerebrovascular and cardiovascular events (cardiovascular disease death including sudden death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, hospitalization for heart failure, or coronary revascularization). The secondary end point was carotid intima-media thickness in a subset of patients.

Results: The incidence of the primary end point showed a trend to be lower in the probucol group compared with that in the control group despite reduced HDL-C without serious adverse events. Anti-atherogenic effects of probucol may be attributed to its potent antioxidative function and enhancement of reverse cholesterol transport.

Conclusion: Since there was no statistical significance between the probucol and control groups despite a marked reduction of HDL-C, further studies on the clinical outcomes of probucol on top of conventional therapy may be necessary in the future (UMIN000003307).
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http://dx.doi.org/10.5551/jat.55327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957028PMC
February 2021

Effects of an Antihypertensive Combination in Japanese Hypertensive Outpatients Based on the Long-acting Calcium Channel Blocker Benidipine on Vascular and Renal Events: A Sub-analysis of the COPE Trial.

Curr Hypertens Rev 2020 ;16(3):238-245

Keio University, Shinjuku-ku, Tokyo, Japan.

Background: In the trial known as COPE (Combination Therapy of Hypertension to Prevent Cardiovascular Events), three benidipine (a Calcium Channel Blocker; CCB) regimens were compared. Hypertensive Japanese outpatients aged 40-85 years (n=3,293) who did not achieve the target blood pressure of <140/90 mmHg with benidipine 4 mg/day were treated with the diuretic thiazide (n=1,094) or a β-blocker (n=1,089) or an additional Angiotensin Receptor Blocker (ARB; n=1,110). A significantly higher incidence of hard cardiovascular composite endpoints and of fatal or non-fatal strokes was observed in the benidipine-β-blocker group compared to the benidipine-thiazide group.

Objective And Methods: We further evaluated the treatment effects of the three benidipine-based regimens on vascular and renal events in a sub-analysis of the COPE patients.

Results: A total of 10 vascular events (0.8 per 1,000 person-years) including one aortic dissection (0.1 per 1,000 person-years) and nine cases of peripheral artery disease (0.8 per 1,000 person-years) were documented, as was a total of seven renal events (0.6 per 1,000 person-years). No significant differences in vascular and renal events were revealed among the three treatment groups: vascular events, p=0.92; renal events, p=0.16, log-rank test.

Conclusion: Blood pressure-lowering therapy with benidipine combined with an ARB, β-blocker, or thiazide was similarly effective in the prevention of vascular and renal events in hypertensive outpatients, although there are not enough events to compare the difference in the three treatment groups.
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http://dx.doi.org/10.2174/1573402116666200129130151DOI Listing
October 2021

High-Dose Versus Low-Dose Pitavastatin in Japanese Patients With Stable Coronary Artery Disease (REAL-CAD): A Randomized Superiority Trial.

Circulation 2018 05;137(19):1997-2009

Department of Integrated Science and Technology for Sustainable Society, Chuo University, Tokyo, Japan (Y. Ohashi).

Background: Current guidelines call for high-intensity statin therapy in patients with cardiovascular disease on the basis of several previous "more versus less statins" trials. However, no clear evidence for more versus less statins has been established in an Asian population.

Methods: In this prospective, multicenter, randomized, open-label, blinded end point study, 13 054 Japanese patients with stable coronary artery disease who achieved low-density lipoprotein cholesterol (LDL-C) <120 mg/dL during a run-in period (pitavastatin 1 mg/d) were randomized in a 1-to-1 fashion to high-dose (pitavastatin 4 mg/d; n=6526) or low-dose (pitavastatin 1 mg/d; n=6528) statin therapy. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. The secondary composite end point was a composite of the primary end point and clinically indicated coronary revascularization excluding target-lesion revascularization at sites of prior percutaneous coronary intervention.

Results: The mean age of the study population was 68 years, and 83% were male. The mean LDL-C level before enrollment was 93 mg/dL with 91% of patients taking statins. The baseline LDL-C level after the run-in period on pitavastatin 1 mg/d was 87.7 and 88.1 mg/dL in the high-dose and low-dose groups, respectively. During the entire course of follow-up, LDL-C in the high-dose group was lower by 14.7 mg/dL than in the low-dose group (<0.001). With a median follow-up of 3.9 years, high-dose as compared with low-dose pitavastatin significantly reduced the risk of the primary end point (266 patients [4.3%] and 334 patients [5.4%]; hazard ratio, 0.81; 95% confidence interval, 0.69-0.95; =0.01) and the risk of the secondary composite end point (489 patients [7.9%] and 600 patients [9.7%]; hazard ratio, 0.83; 95% confidence interval, 0.73-0.93; =0.002). High-dose pitavastatin also significantly reduced the risks of several other secondary end points such as all-cause death, myocardial infarction, and clinically indicated coronary revascularization. The results for the primary and the secondary composite end points were consistent across several prespecified subgroups, including the low (<95 mg/dL) baseline LDL-C subgroup. Serious adverse event rates were low in both groups.

Conclusions: High-dose (4 mg/d) compared with low-dose (1 mg/d) pitavastatin therapy significantly reduced cardiovascular events in Japanese patients with stable coronary artery disease.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01042730.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.032615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959207PMC
May 2018

Rationale and Design of Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) Trial.

Int Heart J 2018 Mar 5;59(2):315-320. Epub 2018 Mar 5.

Jichi Medical University.

Large-scale clinical trials in patients in Western countries with coronary artery disease (CAD) have found that aggressive lipid-lowering therapy using high-dose statins reduces cardiovascular (CV) events further than low-dose statins. However, such evidence has not yet been fully established in Asian populations, including in Japan. The Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study addresses whether intensification of statin therapy improves clinical outcomes in Japanese patients with CAD.REAL-CAD is a prospective, multicenter, randomized, open-label, blinded-endpoint, physician-initiated phase 4 trial in Japan. The study will recruit up to 12,600 patients with stable CAD. Patients are assigned to receive either pitavastatin 1 mg/day or pitavastatin 4 mg/day. LDL-C levels are expected to reach approximate mean values of 100 mg/dL in the low-dose pitavastatin group and 80 mg/dL in the high-dose group. The primary endpoint is the time to occurrence of a major CV event, including CV death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization during an average of 5 years. The large number of patients and the long follow-up period in the REAL-CAD study should ensure that there is adequate power to definitively determine if reducing LDL-C levels to approximately 80 mg/dL by high-dose statin can provide additional clinical benefit.After the study is completed, we will have categorical evidence on the optimal statin dose and target LDL-C level for secondary prevention in Japanese patients.
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http://dx.doi.org/10.1536/ihj.17-557DOI Listing
March 2018

Effects of Calcium-Channel Blocker Benidipine-Based Combination Therapy on Cardiac Events - Subanalysis of the COPE Trial.

Circ J 2018 01 2;82(2):457-463. Epub 2017 Sep 2.

Keio University.

Background: The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial was conducted to compare the effects of regimens combining the dihydropyridine calcium-channel blocker benidipine with each of 3 secondary agent types (an angiotensin-receptor blocker (ARB), a β-blocker and a thiazide) in Japanese hypertensive outpatients who did not achieve target blood pressure (<140/90 mmHg) with benidipine 4 mg/day alone. The analysis included 3,293 patients (ARB, 1,110; β-blocker, 1,089; thiazide, 1,094) with a median follow-up of 3.61 years. The main results of the COPE trial demonstrated that the incidences of hard cardiovascular composite endpoints and fatal or non-fatal strokes were significantly higher in the benidipine/β-blocker group than in the benidipine/thiazide group.Methods and Results:We further evaluated the treatment effects on different cardiac events among the 3 benidipine-based regimens.We observed a total of 50 cardiac events, 4.2 per 1000 person-years. The incidences of total cardiac events and each cardiac event were similarly low among the 3 treatment groups. Unadjusted and multi-adjusted hazard ratios for total cardiac events showed no significant difference among the 3 treatment groups.

Conclusions: This subanalysis of the COPE trial demonstrated that blood pressure-lowering regimens combining benidipine with an ARB, β-blocker or thiazide diuretic were similarly effective for the prevention of cardiac events in Japanese hypertensive outpatients.
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http://dx.doi.org/10.1253/circj.CJ-17-0592DOI Listing
January 2018

Double-Blind, Randomized, Placebo-Controlled Trial Evaluating the Efficacy and Safety of Eplerenone in Japanese Patients With Chronic Heart Failure (J-EMPHASIS-HF).

Circ J 2017 12 19;82(1):148-158. Epub 2017 Aug 19.

St. Hill Hospital.

Background: The mineralocorticoid receptor antagonist eplerenone improved clinical outcomes among patients with heart failure with reduced ejection faction (HFrEF) in the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) study. However, similar efficacy and safety have not been established in Japanese patients. We evaluated the efficacy and safety of eplerenone in patients with HFrEF in a multicenter, randomized, double-blind placebo-controlled outcome study (ClinicalTrials.gov Identifier: NCT01115855). The aim of the study was to evaluate efficacy predefined as consistency of the primary endpoint with that of EMPHASIS-HF at a point estimate of <1 for the hazard ratio.Methods and Results:HFrEF patients with NYHA functional class II-IV and an EF ≤35% received eplerenone (n=111) or placebo (n=110) on top of standard therapy for at least 12 months. The primary endpoint was a composite of death from cardiovascular causes or hospitalization for HF. The primary endpoint occurred in 29.7% of patients in the eplerenone group vs. 32.7% in the placebo group [hazard ratio=0.85 (95% CI: 0.53-1.36)]. Hospitalization for any cause and changes in plasma BNP and LVEF were favorable with eplerenone. A total of 17 patients (15.3%) in the eplerenone group and 10 patients (9.1%) in the placebo group died. Adverse events, including hyperkalemia, were similar between the groups.

Conclusions: Eplerenone was well-tolerated in Japanese patients with HFrEF and showed results consistent with those reported in the EMPHASIS-HF study.
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http://dx.doi.org/10.1253/circj.CJ-17-0323DOI Listing
December 2017

Serial changes in the three-dimensional aspect of the side-branch ostium jailed by a drug-eluting stent assessed by optical coherence tomography.

Int J Cardiovasc Imaging 2017 Jun 6;33(6):797-806. Epub 2017 Feb 6.

Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, Japan.

The present study investigated serial changes in the three-dimensional (3D) aspect of the jailed side-branch (SB) ostium. We evaluated 32 patients who underwent examination with optical coherence tomography (OCT) both at baseline and at follow-up. After reconstruction of the 3D images, we classified the configuration of overhanging struts at the SB orifice into three groups according to the 3D aspect of the jailing configuration. The number of compartments divided by the stent strut was counted. The side-branch flow area (SBFA), i.e., the area of the SB ostium except for jailing struts, was measured by cut-plane analysis. Forty-eight SBs of 25 patients were analyzed. Thirteen SBs were classified as the No-jail type (N-type), 19 as the Simple-jail type (S-type; no longitudinal link at the carina), and 16 as the Complex-jail type (C-type; had a link at the carina). In the N-type, the SBFA was significantly increased at follow-up (P = 0.018). In the C-type, the SBFA was significantly decreased at follow-up (P = 0.002). Percent reduction of SBFA in the C-type group was significantly greater than that in the N-type or S-type groups (S-type vs. C-type P = 0.002, N-type vs. C-type P < 0.001). 3D-OCT images showed that some of the compartments were filled with tissue. The number of compartments was significantly decreased at follow-up (P < 0.001). In the C-type group, the SBFA was significantly decreased and small compartments were filled with tissue. These findings suggest that stent jail complexity is associated with the progression of SB ostial stenosis.
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http://dx.doi.org/10.1007/s10554-017-1080-8DOI Listing
June 2017

Effects of calcium channel blocker benidipine-based combination therapy on target blood pressure control and cardiovascular outcome: a sub-analysis of the COPE trial.

Hypertens Res 2017 Apr 1;40(4):376-384. Epub 2016 Dec 1.

Keio University, Tokyo, Japan.

We compared three benidipine-based regimens-that is, benidipine plus angiotensin receptor blocker (ARB), β-blocker (BB) or thiazide-and found that the benidipine-BB combination was less beneficial in reducing the risk of stroke than the benidipine-thiazide combination. This sub-analysis sought to compare the effects of reaching a target blood pressure (BP) (<140/90 mm Hg) on the cardiovascular outcomes among the three benidipine-based treatment groups in the Combination Therapy of Hypertension to Prevent Cardiovascular Events trial. This sub-analysis included 3001 subjects to evaluate the achievement of target BP at a minimum of three points at 6-month intervals of clinical BP measurements during the study period. After randomization, the patients were categorized into two groups on the basis of achieved on-treatment target BP: a good control (GC) group achieving a BP⩾66.7% of the target and a poor control (PC) group with a BP <66.6% of the target. For each of the two control groups, outcomes were compared among the three treatment groups. The event rates for cardiovascular composite endpoints, stroke and hard cardiovascular events were higher in the PC group than the GC group (P=0.041, P=0.042 and P=0.038, respectively). Within the PC group, hazard ratios for the incidence of cardiovascular events were lower in the benidipine-thiazide group than in the benidipine-BB group (composite cardiovascular events: 2.04, P=0.033; stroke: 4.14, P=0.005; and hard cardiovascular events: 3.52, P=0.009). Within the GC group, the incidence of cardiovascular events was not different among the three treatment regimens. The benidipine-thiazide combination may provide better cardiovascular outcomes than the benidipine-BB combination even in patients with poor BP control.
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http://dx.doi.org/10.1038/hr.2016.158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506236PMC
April 2017

An oxidative stress biomarker, urinary 8-hydroxy-2'-deoxyguanosine, predicts cardiovascular-related death after steroid therapy for patients with active cardiac sarcoidosis.

Int J Cardiol 2016 Jun 17;212:206-13. Epub 2016 Mar 17.

Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Japan.

Background: We investigated whether urinary 8-hydroxy-2'-deoxyguanosine (U-8-OHdG), a marker of oxidative DNA damage, is a prognosticator of cardiovascular-related death in patients with cardiac sarcoidosis (CS).

Methods And Results: In this prospective study, 30 consecutive patients were divided into the active CS (n=20) and non-active CS (n=10) groups, based on abnormal isotope accumulation in the heart on (18)F-fluorodeoxyglucose positron-emission tomography/computed tomography ((18)F-FDG PET/CT) imaging. Nineteen patients in the active CS group underwent corticosteroid therapy. Before corticosteroid therapy initiation, U-8-OHdG, brain natriuretic peptide (BNP), other biomarkers, and indices of cardiac function were measured. Patients were followed-up for a median of 48months. The primary endpoint was the incidence of cardiovascular-related death. During the follow-up period, in the corticosteroid-treated active CS group, 7 of 19 patients experienced cardiovascular-related death. By contrast, in the non-active CS group, 1 of 10 patients died from cardiovascular-related causes. Univariate and multivariate analyses showed that U-8-OHdG and BNP were independent predictors for cardiovascular-related death. The cut-off values for predicting cardiovascular death in corticosteroid-treated patients with active CS were 19.1ng/mg·Cr and 209pg/mL for U-8-OHdG and BNP, respectively. Patients with a U-8-OHdG concentration ≥19.1ng/mg·Cr or a BNP concentration ≥209pg/mL had a significantly higher cardiovascular-related death risk, but U-8-OHdG had better predictive value compared with BNP.

Conclusion: These findings suggested that U-8-OHdG was a powerful predictor of cardiovascular-related death in patients with CS, suggesting that active CS patients with elevated U-8-OHdG levels might be resistant to corticosteroid therapy.
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http://dx.doi.org/10.1016/j.ijcard.2016.03.003DOI Listing
June 2016

Impact of Total Risk Management on Coronary Plaque Regression in Diabetic Patients with Acute Coronary Syndrome.

J Atheroscler Thromb 2016 Aug 8;23(8):922-31. Epub 2016 Mar 8.

Department of Cardiovascular Medicine, Juntendo University School of Medicine.

Aim: Diabetic patients with coronary artery disease have a high incidence of cardiovascular events, which was associated with increased coronary plaque volume. Low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP) play pivotal roles in the progression of coronary plaque. Several trials have shown that intervention for a single risk factor reduced the development of coronary plaque progression. However, it remained uncertain whether total risk management for LDL-C, BP, and glycosylated Hb (HbA1c) has a beneficial effect on coronary plaque volume in diabetic patients.

Methods: This study was a sub-study of the JAPAN-ACS that was a prospective, randomized, open-label trial that evaluated the impact of intensive lipid-lowering therapy on coronary plaque volume in patients with acute coronary syndrome (ACS). Among a total of 252 patients, 73 diabetic patients were analyzed. We examined the impact of total risk management (LDL-C <80 mg/dL, systolic BP <130 mmHg, and HbA1c <6.5%) on changes in coronary plaque volume. The patients were divided into four groups according to the number of risk factors that achieved the target value.

Results: Baseline characteristics were similar among the groups. The degree of coronary plaque regression was greater in patients who achieved total risk management. The number of risk factors that achieved the target level was associated with the extent of the coronary plaque volume reduction in a dose-dependent manner.

Conclusion: Total risk management that focused on LDL-C, BP, and HbA1c had a beneficial impact on the coronary plaque regression in diabetic patients with ACS.
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http://dx.doi.org/10.5551/jat.31948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399291PMC
August 2016

Rationale and Design of the PROSPECTIVE Trial: Probucol Trial for Secondary Prevention of Atherosclerotic Events in Patients with Prior Coronary Heart Disease.

J Atheroscler Thromb 2016 Jun 22;23(6):746-56. Epub 2016 Jan 22.

Department of Community Medicine, Osaka University Graduate School of Medicine.

Background: Reduction of serum LDL-cholesterol by statins was shown to improve clinical outcomes in patients with coronary heart disease (CHD). Although intensive statin therapy significantly reduced cardiovascular risks, atherosclerotic cardiovascular events have not been completely prevented. Therefore, effective pharmacologic therapy is necessary to improve "residual risks" in combination with statins. Probucol has a potent antioxidative effect, inhibits the oxidation of LDL, and reduces xanthomas. Probucol Trial for Secondary Prevention of Atherosclerotic Events in Patients with Prior Coronary Heart Disease (PROSPECTIVE) is a multicenter, randomized, prospective study designed to test the hypothesis that the addition of probucol to other lipid-lowering drugs will prevent cerebro- and cardiovascular events in patients with prior coronary events and high LDL cholesterol levels.

Study Design: The study will recruit approximately 860 patients with a prior CHD and dyslipidemia with LDL-C level ≥140 mg/dl without any medication and those treated with any lipid-lowering drugs with LDL-C level ≥100 mg/dl. Lipid-lowering agents are continuously administered during the study period in control group, and probucol (500 mg/day, 250 mg twice daily) is added to lipid-lowering therapy in the test group. The efficacy and safety of probucol with regard to the prevention of cerebro- and cardiovascular events and the intima-media thickness of carotid arteries as a surrogate marker will be evaluated.

Summary: PROSPECTIVE will determine whether the addition of probucol to other lipid-lowering drugs improves cerebro- and cardiovascular outcomes in patients with prior coronary heart disease. Furthermore, the safety of a long-term treatment with probucol will be clarified.
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http://dx.doi.org/10.5551/jat.32813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399286PMC
June 2016

[Protein-losing enteropathy with systemic lupus erythematosus effectively treated with octreotide and medium chain triglyceride diet: A case report].

Nihon Rinsho Meneki Gakkai Kaishi 2015 ;38(5):421-5

Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine.

In January 2009, a 62-year-old man presented with diarrhea, leg edema, and thrombopenia and was admitted to our hospital. The past medical history revealed Sjögren's syndrome and autoimmune hepatitis for which he had been administered prednisolone. On admission, a laboratory examination revealed massive hypoalbuminemia and high levels of C-reactive protein and platelet-associated IgG. Anti-double stranded DNA and anti-Sm antibodies were negative. Analysis of the bone marrow aspirate and Tc-99m albumin scintigraphy findings suggested autoimmune thrombocytopenic purpura (AITP) and protein-losing enteropathy (PLE), respectively. We diagnosed him as SLE, because past immunoserological testing had showed positivity for anti-double stranded DNA antibody and LE cells. Methylprednisolone pulse therapy and intravenous immunoglobulin therapy were ineffective. Rituximab was ineffective against PLE but was effective against AITP. Cyclosporine and Cyclophosphamide were ineffective against PLE. Subcutaneous injection of 200-μg octreotide daily and a medium chain triglyceride (MCT) diet was effective against PLE, and the patient's condition dramatically improved. The effectiveness of octreotide treatment and an MCT diet in the treatment of PLE with SLE is discussed.
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http://dx.doi.org/10.2177/jsci.38.421DOI Listing
September 2016

Noninvasive assessment of exercise tolerance using mitral annular velocities.

J Med Ultrason (2001) 2016 Jan 16;43(1):37-45. Epub 2015 Sep 16.

Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Japan.

Purpose: To investigate the feasibility of evaluating exercise tolerance using lateral and septal mitral annular velocities in patients with preserved left ventricular ejection fraction (LVEF) and those with reduced LVEF.

Method: We studied 36 patients with LVEF ≥50% and 36 with LVEF <50%. We measured peak early diastolic velocity of transmitral flow (E) and peak early diastolic velocities of the lateral (LEa) and septal (SEa) mitral annulus. The ratios of E to LEa (E/LEa) and E to SEa (E/SEa) were calculated. We measured peak oxygen consumption [Formula: see text] and anaerobic threshold (AT) by cardiopulmonary exercise testing.

Results: In patients with LVEF ≥50%, E/LEa correlated well with [Formula: see text] and AT (r = -0.69 and r = -0.74, respectively; p < 0.001); E/SEa correlated modestly (r = -0.59 and r = -0.60, respectively; p < 0.001). In patients with LVEF <50%, E/LEa correlated well with [Formula: see text] and AT (r = -0.72 and r = -0.76; respectively, p < 0.001); E/SEa correlated modestly (r = -0.63 and r = -0.63, respectively; p < 0.001).

Conclusion: E/LEa may be more useful than E/SEa for the noninvasive estimation of exercise tolerance, throughout a wide range of LVEF.
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http://dx.doi.org/10.1007/s10396-015-0672-yDOI Listing
January 2016

Neural crest-derived resident cardiac cells contribute to the restoration of adrenergic function of transplanted heart in rodent.

Cardiovasc Res 2016 Mar 8;109(3):350-7. Epub 2015 Dec 8.

Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

Aims: We investigated whether neural crest-derived cardiac resident cells contribute to the restoration of intrinsic adrenergic function following transplantation in mice. Transplanted heart shows partial restoration of cardiac adrenergic activity with time. Both the intrinsic cardiac adrenergic system and extrinsic sympathetic re-innervation contribute to neuronal remodelling in the transplanted heart. Little is known about the origin and function of the intrinsic system in the transplanted heart.

Methods And Results: Heart from the protein 0-Cre/Floxed-Enhanced Green Fluorescent Protein double-transgenic mouse was transplanted onto the abdominal aorta of the non-obese diabetic/severe combined immunodeficient mouse to trace the fate of cardiac resident neural crest-derived cells. Sympathetic nerve fibres, which are predominantly localized to the epicardial surface of the heart, disappeared in the transplanted heart. Intramyocardial neural crest cells increased immediately, while neural crest-derived nucleated tyrosine hydroxylase (TH)-immunoreactive cells increased over 2 weeks following transplantation. The mRNA expression levels of TH, dopamine-β-hydroxylase and phenylethanolamine N-methyltransferase, and the tissue content of catecholamines in the transplanted hearts increased with time in association with an increase in the number of neural crest-derived nucleated TH-immunoreactive cells and tissue nerve growth factor levels. Iodine-123-metaiodobenzylguanidine scintigraphy showed that the uptake ability of transplanted heart for catecholamines also recovered with time. Finally, the chronotropic response to tyramine both in vivo and ex vivo reappeared 2 weeks after transplantation.

Conclusion: Neural crest-derived adrenergic cells increased following heart transplantation. The restoration of cardiac sympathetic activities in transplanted heart is tightly coupled with an increase in the number of neural crest-derived adrenergic cells.
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http://dx.doi.org/10.1093/cvr/cvv267DOI Listing
March 2016

Effects of calcium channel blocker-based combinations on intra-individual blood pressure variability: post hoc analysis of the COPE trial.

Hypertens Res 2016 Jan 22;39(1):46-53. Epub 2015 Oct 22.

Keio University, Tokyo, Japan.

Visit-to-visit blood pressure (BP) variability is an important predictor of stroke. However, which antihypertensive drug combination is better at reducing visit-to-visit BP variability and therefore at reducing stroke incidence remains uncertain. We have previously reported that the dihydropyridine calcium channel blocker benidipine combined with a β-blocker appeared to be less beneficial in reducing the risk of stroke than a combination of benidipine and thiazide. Here, we further compare the visit-to-visit BP variability among three benidipine-based regimens, namely angiotensin receptor blocker (ARB), β-blocker and thiazide combinations. The present post hoc analysis included 2983 patients without cardiovascular events or death during the first 18 months after randomization. We compared the BP variability (defined as the s.d. and the coefficient of variation (CV)), maximum systolic BP (SBP) and diastolic BP (DBP) of the clinic mean on-treatment BPs obtained at 6-month intervals, starting 6 months after the treatment initiation, among the 3 treatments (ARB, n=1026; β-blocker, n=966; thiazide, n=991). During the first 6-36 months after randomization, both the s.d. and CV-BPs were lower in the benidipine-thiazide group than in the benidipine-β-blocker group (s.d.-SBP, P=0.019; s.d.-DBP, P=0.030; CV-SBP, P=0.012; CV-DBP, P=0.022). The s.d. and CV in the ARB group did not reach statistical significance compared with the other two groups. The maximum BPs did not differ among the three treatments. These findings suggest that the benidipine-thiazide combination may reduce visit-to-visit BP variability more than the benidipine-β-blocker combination.
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http://dx.doi.org/10.1038/hr.2015.104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709460PMC
January 2016

Urinary 8-hydroxy-2'-deoxyguanosine as a novel biomarker of inflammatory activity in patients with cardiac sarcoidosis.

Int J Cardiol 2015 17;190:319-28. Epub 2015 Apr 17.

Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Japan.

Background: Inflammation and oxidative stress play a crucial role in the pathogenesis of cardiac sarcoidosis (SAR). We investigated whether urinary (U) 8-hydroxy-2'-deoxyguanosine (8-OHdG)--an oxidative DNA damage marker--was related to SAR inflammatory activity.

Methods: U-8-OHdG levels were measured in 31 SAR patients, classified as active (n=17) or non-active (n=14) based on (18)F-fluorodeoxyglucose positron emission tomography-computed tomography ((18)F-FDG-PET/CT), 28 dilated cardiomyopathy (DCM) patients, and 30 controls. In active SAR patients, U-8-OHdG levels were reexamined and compared with (18)F-FDG-PET/CT results at 6 months after corticosteroid treatment to assess therapeutic response.

Results: Immunohistochemical examination of left ventricle (LV) autopsy samples from SAR patients revealed positive 8-OHdG staining in cardiomyocyte nuclei from LV sections showing (18)F-FDG accumulation on PET/CT, while serum 8-OHdG levels were significantly higher in the coronary sinus than in the aortic root only in active SAR patients. U-8-OHdG levels in SAR patients were higher than those in controls, and significantly higher in active SAR patients than in non-active SAR and DCM patients. U-8-OHdG was a powerful predictor of active SAR in receiver operating characteristic curve analysis (AUC, 0.98; 95% CI, 0.94-1.02; optimal cutoff value, 13.1 ng/mg creatinine), with a sensitivity of 88.2% and a specificity of 92.9%. U-8-OHdG levels in responders significantly decreased at 6 months after corticosteroid treatment initiation, in proportion with the decrease in the focal cardiac uptake of (18)F-FDG.

Conclusions: U-8-OHdG is a potentially clinically useful biomarker for evaluating inflammatory activity and monitoring the effectiveness of corticosteroid therapy in SAR patients.
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http://dx.doi.org/10.1016/j.ijcard.2015.04.144DOI Listing
February 2016

TLR4 is a critical regulator of angiotensin II-induced vascular remodeling: the roles of extracellular SOD and NADPH oxidase.

Hypertens Res 2015 Oct 9;38(10):649-55. Epub 2015 Apr 9.

Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.

Toll-like receptor 4 (TLR4) and angiotensin II (AngII) induce vascular remodeling through the production of reactive oxygen species (ROS). AngII has also been shown to increase antioxidant enzyme extracellular superoxide dismutase (ecSOD). However, the roles of TLR4 in Ang II-induced ROS production, vascular remodeling and hypertension remain unknown. Mice lacking TLR4 function showed significant inhibition of vascular remodeling in response to chronic AngII infusion, with no impact on blood pressure. The increases in ROS level and NADPH oxidase activity in response to AngII infusion were markedly blunted in TLR4-deficient mice. Similar effects were observed in wild-type (WT) mice treated with a sub-depressor dose of the AT1 receptor antagonist irbesartan, which had no effects on TLR4-deficient mice. Intriguingly, the AngII infusion-induced increases in ecSOD activity and expression were rather enhanced in TLR4-deficient mice compared with WT mice, whereas the expression of the proinflammatory chemokine MCP-1 was decreased. Importantly, AngII-induced vascular remodeling was positively correlated with NADPH oxidase activity, ROS levels and MCP-1 expression levels. Notably, chronic norepinephrine infusion, which elevates blood pressure without increasing ROS production, did not induce significant vascular remodeling in WT mice. Taken together, these findings suggest that ROS elevation is required for accelerating vascular remodeling but not for hypertensive effects in this model. We demonstrated that TLR4 plays a pivotal role in regulating AngII-induced vascular ROS levels by inhibiting the expression and activity of the antioxidant enzyme ecSOD, as well as by activating NADPH oxidase, which enhances inflammation to facilitate the progression of vascular remodeling.
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http://dx.doi.org/10.1038/hr.2015.55DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533692PMC
October 2015

Angiotensin Ⅱ Activates MCP-1 and Induces Cardiac Hypertrophy and Dysfunction via Toll-like Receptor 4.

J Atheroscler Thromb 2015 Aug 5;22(8):833-44. Epub 2015 Mar 5.

Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine.

Aim: Angiotensin Ⅱ(Ang Ⅱ) produces reactive oxygen species (ROS), thus contributing to the development of cardiac hypertrophy and subsequent heart failure, and stimulates the expression of monocyte chemoattractant protein-1 (MCP-1). In addition, Toll-like receptor 4 (TLR4) is involved in the upregulation of MCP-1. In order to clarify whether TLR4 is involved in the onset of cardiac dysfunction caused by Ang Ⅱ stimulation, we investigated the effects of TLR4 on oxidative stress, the MCP-1 expression and cardiac dysfunction in mice with Ang Ⅱ-induced hypertension.

Methods: TLR4-deficient (Tlr4(lps-d)) and wild-type (WT) mice were randomized into groups treated with Ang Ⅱ, norepinephrine (NE) or a subdepressor dose of the Ang Ⅱreceptor blocker irbesartan (IRB) and Ang Ⅱ for two weeks.

Results: Ang Ⅱ and NE similarly increased systolic blood pressure in all drug-treated groups compared to that observed in the control group among both WT and Tlr4(lps-d) mice (p<0.05). In the WT mice, Ang Ⅱ induced cardiac hypertrophy as well as vascular remodeling and perivascular fibrosis of the intramyocardial arteries and monocyte/macrophage infiltration in the heart (p<0.05). Furthermore, Ang Ⅱ treatment decreased the left ventricular diastolic function and resulted in a greater left ventricular end-systolic dimension (p<0.05) in addition to producing a five-fold increase in the NADPH oxidase activity, ROS content and MCP-1 expression (p<0.05). In contrast, the Tlr4(lps-d) mice showed little effects of Ang Ⅱ on these indices. In the WT mice, IRB treatment reversed these changes compared to that seen in the mice treated with Ang Ⅱ alone. NE produced little effect on any of the indices in either the WT or Tlr4(lps-d) mice.

Conclusions: TLR4 may be involved in the processes underlying the increased oxidative stress, selectively activated MCP-1 expression and cardiac hypertrophy and dysfunction seen in cases of Ang Ⅱ- induced hypertension.
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http://dx.doi.org/10.5551/jat.27292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509415PMC
August 2015

Comparison of neointimal coverage and extra-stent lumen between sirolimus and everolimus-eluting stent using optical coherence tomography.

Heart Vessels 2016 Apr 23;31(4):449-56. Epub 2015 Jan 23.

Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, Japan.

The external lumen of a stent [defined as extra-stent lumen (ESL)] assessed by optical coherence tomography (OCT) may be related to the risk of thrombus formation after sirolimus-eluting stent (SES) implantation. An everolimus-eluting stent (EES) might provide relatively minimal inflammatory reaction and appropriate neointimal coverage. The purpose of this study was to compare the neointimal thickness and ESL between SES and EES. Patients who underwent OCT examination more than 7 months after either SES or EES implantation were enrolled. Stent area (SA), lumen area (LA), neointimal area (NIA) and neointimal thickness (NIT) of each strut were measured at 1-mm intervals between stented segments. The area, angle (summation per cross-section) and depth (maximum distance from adjacent vessel surface to the outline of stent) of ESL were analyzed. A total of 49 lesions were included (SES n = 20, EES n = 29). Mean follow-up period was 11 months. A total of 998 cross-sections and 9874 struts were analyzed. There were no differences in stent area, lumen area and neointimal area (SA: 6.01 ± 1.60 vs. 6.02 ± 1.40 mm(2), p = 0.572, LA: 5.37 ± 1.52 vs. 5.29 ± 1.34 mm(2), p = 0.692, NIA: 0.64 ± 0.49 vs. 0.72 ± 0.37 mm(2), p = 0.493). Mean NIT of SES and EES were 0.11 ± 0.05 and 0.10 ± 0.05 mm, respectively (p = 0.367). Conversely, area, angle and depth of ESL in SES group were significantly greater than those in EES group (0.20 ± 0.39 vs. 0.03 ± 0.09 mm(2), p < 0.001, 56.2 ± 59.1° vs. 20.1 ± 41.9°, p < 0.001, 0.10 ± 0.09 vs. 0.03 ± 0.03 mm, p < 0.001). OCT showed that the efficacy of neointimal growth suppression is similar between SES and EES, whereas the adverse vascular response after EES implantation is smaller than that after SES implantation.
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http://dx.doi.org/10.1007/s00380-015-0630-zDOI Listing
April 2016

New quantitative method to diagnose coronary in-stent restenosis by 64-multislice computed tomography.

J Cardiol 2015 Jan 18;65(1):57-62. Epub 2014 May 18.

Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Japan.

Background: The aim of this study is to evaluate the accuracy of a newly developed quantitative method using 64-multislice computed tomography angiography (CTA) to detect coronary in-stent restenosis (ISR).

Methods And Results: CTA was performed in 45 patients who underwent stent implantation (79 lesions) and the accuracy to diagnose ISR was evaluated by comparing with invasive coronary angiography (ICA). CTA was evaluated both visually and quantitatively using a new stent restenosis index (SRI) utilizing CT densities at proximal and distal artery lumen from the stented region and the correction value depending on the stent diameter. ICA showed 11 ISR (14%). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for visual evaluation were 78%, 75%, 35%, 95%, and 76%, respectively. On the other hand, the quantitative evaluation using SRI represents 82%, 93%, 64%, 97%, and 91%, respectively.

Conclusions: Evaluation of ISR using SRI is superior to the visual estimation of CTA.
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http://dx.doi.org/10.1016/j.jjcc.2014.03.013DOI Listing
January 2015

Assessment of the aortic valve annular geometry by real-time three-dimensional transthoracic echocardiography: comparison with two-dimensional transthoracic echocardiography and multidetector computed tomography.

J Echocardiogr 2014 Mar 23;12(1):24-30. Epub 2013 Nov 23.

Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Japan.

Background: Real-time three-dimensional transthoracic echocardiography (3DTTE) has been developed and provides detailed 3D information, noninvasively. However, the accuracy and usefulness of 3DTTE in the evaluation of aortic root geometry are still not clear.

Methods: 2DTTE and 3DTTE were performed in 161 patients with various cardiac diseases. Multidetector computed tomography (MDCT) was performed in 35 of the 161 patients. The diameters and areas of the aortic annulus were evaluated by these three methods and compared. To evaluate the shape of the aortic annuli, eccentricity index (EI) (1 - minimum diameter/long-axis diameter) were calculated.

Results: Maximum dimensions of the aortic annulus measured by MDCT were significantly larger than those by 3DTTE and 2DTTE. The aortic annular areas measured by MDCT and 3DTTE were significantly larger than areas by 2DTTE. A good correlation (r = 0.85) was observed between the areas obtained by 3DTTE and MDCT; however, the correlation between the values by 2DTTE and MDCT was rough (r = 0.44). EI values in 46 % of the patients were greater than 0.1, i.e., the aortic annulus was elliptical.

Conclusion: The images obtained by 3DTTE provided accurate values of the aortic annular area, which were equal to the values measured by MDCT. 3DTTE is a useful method to evaluate the aortic annular geometry.
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http://dx.doi.org/10.1007/s12574-013-0197-6DOI Listing
March 2014

Tenascin C protects aorta from acute dissection in mice.

Sci Rep 2014 Feb 11;4:4051. Epub 2014 Feb 11.

1] Department of Molecular Cardiovascular Biology, Yamaguchi University School of Medicine [2] Cardiovascular Research Institute, Kurume University.

Acute aortic dissection (AAD) is caused by the disruption of intimomedial layer of the aortic walls, which is immediately life-threatening. Although recent studies indicate the importance of proinflammatory response in pathogenesis of AAD, the mechanism to keep the destructive inflammatory response in check is unknown. Here, we report that induction of tenascin-C (TNC) is a stress-evoked protective mechanism against the acute hemodynamic and humoral stress in aorta. Periaortic application of CaCl₂ caused stiffening of abdominal aorta, which augmented the hemodynamic stress and TNC induction in suprarenal aorta by angiotensin II infusion. Deletion of Tnc gene rendered mice susceptible to AAD development upon the aortic stress, which was accompanied by impaired TGFβ signaling, insufficient induction of extracellular matrix proteins and exaggerated proinflammatory response. Thus, TNC works as a stress-evoked molecular damper to maintain the aortic integrity under the acute stress.
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http://dx.doi.org/10.1038/srep04051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3920275PMC
February 2014

A low-dose β1-blocker effectively and safely slows the heart rate in patients with acute decompensated heart failure and rapid atrial fibrillation.

Cardiology 2014 26;127(2):105-13. Epub 2013 Nov 26.

Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Japan.

Objective: Recently, we reported that low-dose landiolol (1.5 µg·kg(-1)·min(-1)), an ultra-short-acting β-blocker, safely decreased the heart rate (HR) in patients with acute decompensated heart failure (ADHF) and sinus tachycardia, thereby improving cardiac function. We investigated whether low-dose landiolol effectively decreased the HR in ADHF patients with rapid atrial fibrillation (AF).

Methods: We enrolled 23 ADHF patients with rapid AF (HR ≥120 beats·min(-1) and New York Heart Association class III-IV) and systolic heart failure (SHF: n = 12) or diastolic heart failure (DHF: n = 11) who received conventional therapy with diuretics, vasodilators, and/or low-dose inotropes. They were administered continuous intravenous infusion of low-dose landiolol (1.0-2.0 µg·kg(-1)·min(-1)), and their electrocardiograms and blood pressures were monitored for 24 h thereafter.

Results: Two hours after starting landiolol, the HR was reduced significantly (22%), without a reduction in blood pressure, and remained constant thereafter. The HR reduction 2 h after landiolol administration was significantly greater in the DHF group than in the SHF group. No incidence of hypotension was recorded.

Conclusions: Digitalis or amiodarone is currently recommended for HR control in ADHF patients with rapid AF. Our results showed that continuous infusion of low-dose landiolol may also be useful as first-line therapy in these patients.
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http://dx.doi.org/10.1159/000355312DOI Listing
September 2014

Sequel of jailed side branch.

Circ J 2014 29;78(3):772-4. Epub 2013 Nov 29.

Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine.

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http://dx.doi.org/10.1253/circj.cj-13-0709DOI Listing
December 2014

Impact of physical activity on cardiovascular events in patients with chronic heart failure. A multicenter prospective cohort study.

Circ J 2013 27;77(12):2963-72. Epub 2013 Sep 27.

Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine.

Background: We have previously demonstrated that the prevalence of metabolic syndrome in chronic heart failure (CHF) is more than double compared with the general population in Japan. However, the impact of physical activity on cardiovascular events in CHF patients remains to be fully elucidated.

Methods And Results: We performed a prospective, nationwide large-scale multicenter study of 9,178 patients with stage A/B/C/D CHF in Japan. We obtained the baseline physical activity data for 7,292 and yearly changes in physical activity data during a 3-year follow-up period for 4,353 patients. We divided the patients into high- and low-exercise groups by using the median value of physical activity in the stage A/B and C/D groups. In both groups, patients who exercised more were characterized by younger age and less advanced stage of CHF. Importantly, the baseline physical activity levels were significantly associated with all-cause death, heart failure (HF) hospitalization and other cardiovascular events (except acute myocardial infarction, stroke, HF hospitalization). Furthermore, the yearly change in physical activity level was also significantly associated with HF hospitalization and other cardiovascular events in both groups.

Conclusions: The baseline level of physical activity and its yearly changes are significantly associated with all-cause death and major cardiovascular events in both stage A/B and C/D patients, suggesting that physical activity could be an important therapeutic target to improve the long-term prognosis of CHF patients.
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http://dx.doi.org/10.1253/circj.cj-13-0746DOI Listing
July 2014

Nonbacterial thrombotic endocarditis demonstrated by repeat echocardiography.

J Med Ultrason (2001) 2013 Oct 2;40(4):453-7. Epub 2013 Mar 2.

Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Japan.

We report a case of nonbacterial thrombotic endocarditis (NBTE) in a patient with bladder cancer presenting with multiple cerebral infarctions. Initial transthoracic and transesophageal echocardiography did not show any abnormalities. However, repeat transthoracic and transesophageal echocardiography demonstrated a vegetation on the anterior leaflet of the mitral valve with mild mitral regurgitation and no evidence of leaflet destruction. Persistent high-grade fevers and leukocytosis were observed. The patient was suspected to have infective endocarditis. However, abdominal ultrasound and computed tomography scan revealed multiple metastatic masses, and serial blood cultures were negative. The patient was ultimately diagnosed with NBTE associated with multiple metastases of bladder cancer. This case suggests that even if echocardiography does not initially demonstrate any abnormalities in patients with embolism, it must be repeated at the recurrence of embolism, and that even if clinical signs of infection are documented, NBTE should be suspected in any cancer patient with thromboembolic events.
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http://dx.doi.org/10.1007/s10396-013-0437-4DOI Listing
October 2013

Effects of a benidipine-based combination therapy on the risk of stroke according to stroke subtype: the COPE trial.

Hypertens Res 2013 Dec 29;36(12):1088-95. Epub 2013 Aug 29.

Center for Clinical Research, Yamaguchi University Hospital, Ube, Japan.

The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial compared the dihydropyridine T/L-type calcium channel blocker benidipine-based therapies when combined with an angiotensin receptor blocker (ARB), a β-blocker (BB) or a thiazide diuretic (TD). The results suggested that benidipine combined with a BB appeared to be less beneficial in reducing the risk of stroke compared with the benidipine-TD combination (hazard ratio (HR): 2.31, P=0.0109). We further evaluated the treatment effects on different stroke subtypes among the three benidipine-based regimens. The COPE trial was an investigator-initiated, multicenter study with PROBE design. Patients with atrial fibrillation or flutter were excluded from the study. All stroke events were subclassified with the Trial of Org 10,172 in Acute Stroke Treatment (TOAST) criteria. The total incidence of stroke was 4.7, hemorrhagic stroke was 1.6 and ischemic stroke was 2.5 per 1000 person-years. The incidence of lacunar stroke was 1.1, large-artery stroke was 0.6, cardioembolic stroke was 0.3, unknown ischemic type was 0.6 and transient ischemic attack was 0.6 per 1000 person-years. Although few differences in stroke subtypes were observed among the three treatment groups, multi-adjusted HRs for the incidence rates of all types of stroke, hemorrhagic stroke and ischemic stroke were significantly higher with the benidipine-BB regimen than with the benidipine-TD regimen. The incidence of both hemorrhagic and ischemic stroke in the benidipine-ARB regimen was not different compared with the other two treatment regimens. This prespecified sub-analysis suggested that a blood pressure-lowering therapy with a benidipine-TD regimen might be beneficial for hypertensive patients to prevent both hemorrhagic and ischemic stroke.
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http://dx.doi.org/10.1038/hr.2013.100DOI Listing
December 2013

Combination therapy for hypertension in patients with CKD: a subanalysis of the Combination Therapy of Hypertension to Prevent Cardiovascular Events trial.

Hypertens Res 2013 Nov 18;36(11):947-58. Epub 2013 Jul 18.

Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Japan.

The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial was a multicenter, randomized, three-arm comparative study (N=3293) undertaken to determine the optimal combination therapy, based on the occurrence of cardiovascular events in patients treated with an angiotensin II receptor blocker (ARB), a β-blocker (BB) or a thiazide diuretic (TD) in addition to the calcium antagonist benidipine as baseline medication. This subanalysis was conducted to compare the efficacy of three combination therapies in a subset of 834 patients with chronic kidney disease (CKD) (287 patients treated with benidpine-ARB, 283 patients treated with benidipine-BB and 264 patients treated with benidipine-TD). The incidence of composite cardiovascular events as the primary end point did not differ among these three groups. The incidence of hard end points and cerebrovascular events among these groups did not differ either, although the incidence among all patients in the COPE trial was lower in the benidipine-TD group than in the benidipine-BB group. The incidence of new-onset diabetes mellitus was higher in the benidipine-TD group than in the benidipine-ARB group among patients with CKD. The estimated glomerular filtration rate (eGFR) was maintained even after 12 months of treatment in patients with a baseline eGFR <60 ml min(-1) per 1.73 m(2) regardless of the treatment group, although the eGFR decreased over time in all patients in the three groups. In conclusion, in patients with CKD, all of the tested combination therapies demonstrated comparable efficacy in terms of prevention of cardiovascular events as well as maintenance of eGFR.
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http://dx.doi.org/10.1038/hr.2013.63DOI Listing
November 2013
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