Takayuki Yokoyama

Early Statin Treatment in Patients With Acute Coronary Syndrome: Demonstration of the Beneficial Effect on Atherosclerotic Lesions by Serial Volumetric Intravascular Ultrasound Analysis During Half a Year After Coronary Event: The ESTABLISH Study

Background—Recent clinical trials have demonstrated that aggressive lipid lowering by statins could prevent recurrent events after acute coronary syndrome (ACS). We hypothesized that this efficacy was caused by a significant reduction in plaque volume by aggressive LDL cholesterol (LCL-C) lowering. The present study investigated the effect of early statin treatment on plaque volume of a nonculprit lesion by serial volumetric intravascular ultrasound in patients with ACS. Methods and Results—Seventy patients with ACS were enrolled. All patients underwent emergency coronary angiography and percutaneous coronary intervention (PCI). They were randomized to intensive lipid-lowering therapy (n=35; atorvastatin 20 mg/d) or control (n=35) groups after PCI. Volumetric intravascular ultrasound analyses were performed at baseline and 6-month follow-up for a non-PCI site in 48 patients (atorvastatin, n=24; control, n=24). LDL-C level was significantly decreased by 41.7% in the atorvastatin group compared with the control group, in which LDL-C was increased by 0.7% (P<0.0001). Plaque volume was significantly reduced in the atorvastatin group (13.1±12.8% decrease) compared with the control group (8.7±14.9% increase; P<0.0001). Percent change in plaque volume showed a significant positive correlation with follow-up LDL-C level (R=0.456, P=0.0011) and percent LDL-C reduction (R=0.612, P<0.0001), even in patients with baseline LDL-C <125 mg/dL. Conclusions—Early aggressive lipid-lowering therapy by atorvastatin for 6 months significantly reduced the plaque volume in patients with ACS. Percent change in plaque volume showed a significant positive correlation with percent LDL-C reduction, even in patients with low baseline LDL-C.

Early intensive statin treatment for six months improves long-term clinical outcomes in patients with acute coronary syndrome (Extended-ESTABLISH trial): A follow-up study

BACKGROUND The ESTABLISH trial found using volumetric intravascular ultrasound that atorvastatin therapy started early and continued for 6 months significantly reduced plaque volume in patients with acute coronary syndrome (ACS). However, the benefits of early statin administration on long-term outcomes remain unclear. We therefore examined whether the early initiation of statin in patients with ACS improves long-term prognosis. METHODS AND RESULTS The Extended-ESTABLISH trial included 180 patients with ACS who underwent emergency percutaneous coronary intervention (PCI). These patients were randomized here to groups given either early intensive lipid-lowering therapy (n=90; atorvastatin 20 mg/day) or standard care (control, n=90) within 48 h of events. Baseline characteristics between the two groups did not significantly differ at the time of ACS onset. Six months after PCI, all patients were treated with statins to achieve an LDL-C value of <100 mg/dL. We compared the first occurrence of major adverse cardiac and cerebrovascular events (MACCE). Prognostic data were fully documented during the entire follow-up period (mean, 1538+/-707 days). Cumulative event-free survival was significantly higher in the atorvastatin, than in the control group (p=0.041; log-rank test). Furthermore, by adjusting for validated prognosticators, early statin administration was identified as a good predictor of MACCE (HR 0.46, 95%CI 0.23-0.86; p=0.015). CONCLUSIONS In-hospital initiation of statin therapy immediately after ACS conferred long-term benefits and 6 months of intensive lipid-lowering therapy improved long-term clinical outcomes after PCI in patients with ACS.

Long-term impact of mild chronic kidney disease in patients with acute coronary syndrome undergoing percutaneous coronary interventions

BACKGROUND Accumulating evidence shows that chronic kidney disease (CKD) is an independent risk factor for major adverse cardiac and cerebrovascular events (MACCE) after acute coronary syndrome (ACS). However, it is not known whether mild renal insufficiency affects long-term clinical outcomes. METHODS This is a post-hoc analysis from the Extended-ESTABLISH trial, which was designed to estimate the impact of renal insufficiency on patients with ACS after percutaneous coronary intervention over the long term. One hundred and eighty patients were divided into three groups based on the estimated glomerular filtration rate (eGFR) at time of ACS: moderate-to-severe CKD, <60 mL/min/1.73 m(2) (n = 31, 17.2%); mild CKD, 60-90 mL/min/1.73 m(2) (n = 100, 55.6%) and non-CKD, ≥90 mL/min/1.73 m(2) (n = 47, 26.1%). The eGFR was calculated using the new Japanese equation. Long-term outcomes were compared over a follow-up period of 1538 ± 707 days. RESULTS Cumulative incidence rates of MACCE did not significantly differ between groups 1 year after ACS onset (P = 0.384), whereas significant differences appeared during the long-term follow-up (10.6 versus 27.0% versus 35.4% in the non-CKD, mild CKD and moderate-to-severe CKD groups, respectively; log-rank test, P = 0.022). In a multivariate Cox hazard regression model, moderate-to-severe CKD and mild CKD were associated with a higher rate of MACCE after adjusting for confounding variables (hazard ratios = 3.46 and 2.67, respectively; P = 0.043). CONCLUSIONS The presence of mild CKD at ACS occurrence is associated with a worse outcome in the long term, but not the short term.

Decreased circulating lipoprotein-associated phospholipase A2 levels are associated with coronary plaque regression in patients with acute coronary syndrome

OBJECTIVE Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a vascular-specific inflammatory enzyme, of which increases are associated with cardiovascular events. However, the relationship between circulating Lp-PLA2 levels and coronary plaque volume has not been clarified in patients with acute coronary syndrome (ACS). METHODS We studied 40 patients with ACS (age, 61.4 ± 8.0 years; male, 87.5%; statin use, 45.0%) who had undergone successful percutaneous coronary intervention (PCI). Plaque volume (PV) in non-culprit sites of PCI lesions was precisely determined using grayscale intravascular ultrasound (IVUS) at onset and at six months later. We then analyzed associations among PV, lipid profiles and Lp-PLA2 levels. RESULTS Circulating Lp-PLA2 levels and PV significantly decreased between baseline and six months of follow-up (458.6 ± 166.7 IU/L vs. 378.4 ± 158.5 IU/L, p < 0.001 and 82.2 ± 34.8mm(3) vs. 77.3 ± 33.1mm(3), p < 0.001, respectively). The % change in PV positively and significantly correlated with % change in LDL-C and in the LDL-C/HDL-C ratio (r = 0.444, p = 0.004 and r = 0.462, p = 0.003, respectively). Furthermore, % changes in Lp-PLA2 and in PV correlated even more closely (r = 0.496, p = 0.001). The absolute change in PV also significantly correlated with the change in Lp-PLA2 levels (r = 0.404, p = 0.009). CONCLUSIONS Circulating Lp-PLA2 levels are associated with changes in coronary plaque determined by IVUS in patients with ACS.

Low high-density lipoprotein cholesterol is a residual risk factor associated with long-term clinical outcomes in diabetic patients with stable coronary artery disease who achieve optimal control of low-density lipoprotein cholesterol

Diabetes mellitus is recognized an independent risk factor for coronary artery disease (CAD) and mortality. Clinical trials have shown that statins significantly reduce cardiovascular events in diabetic patients. However, residual cardiovascular risk persists despite the achievement of target low-density lipoprotein cholesterol (LDL-C) levels with statin. High-density lipoprotein cholesterol (HDL-C) is an established coronary risk factor that is independent of LDL-C levels. We evaluated the impact of HDL-C on long-term mortality in diabetic patients with stable CAD who achieved optimal LDL-C. We enrolled 438 consecutive diabetic patients who were scheduled for percutaneous coronary intervention between 2004 and 2007 at our institution. We identified 165 patients who achieved target LDL-C <100 mg/dl. Patients were stratified into two groups according to HDL-C levels (low HDL-C group, baseline HDL-C <40 mg/dl; high HDL-C group, ≥40 mg/dl). Major adverse cardiac events (MACE) that included all-cause death, acute coronary syndrome, and target lesion revascularization were evaluated between the two groups. The median follow-up period was 946 days. The rate of MACE was significantly higher in diabetic patients with low-HDL-C who achieved optimal LDL-C (6.9 vs 17.9 %, log-rank P = 0.030). Multivariate Cox regression analysis showed that HDL-C is significantly associated with clinical outcomes (adjusted hazard ratio for MACE 1.33, 95 % confidence interval 1.01–1.75, P = 0.042). Low HDL-C is a residual risk factor that is significantly associated with long-term clinical outcomes among diabetic patients with stable CAD who achieve optimal LDL-C levels.

Association between myocardial triglyceride content and cardiac function in healthy subjects and endurance athletes.

Ectopic fat accumulation plays important roles in various metabolic disorders and cardiovascular diseases. Recent studies reported that myocardial triglyceride (TG) content measured by proton magnetic resonance spectroscopy (1H-MRS) is associated with aging, diabetes mellitus, and cardiac dysfunction. However, myocardial TG content in athletes has not yet been investigated. We performed 1H-MRS and cardiac magnetic resonance imaging in 10 male endurance athletes and 15 healthy male controls. Serum markers and other clinical parameters including arterial stiffness were measured. Cardiopulmonary exercise testing was also performed. There were no significant differences in clinical characteristics including age, anthropometric parameters, blood test results, or arterial stiffness between the two groups. Peak oxygen uptakes, end–diastolic volume (EDV), end–systolic volume (ESV), left ventricular (LV) mass, peak ejection rates and peak filling rates were significantly higher in the athlete group than in the control group (all P<0.02). Myocardial TG content was significantly lower in the athlete group than in the control group (0.60±0.20 vs. 0.89±0.41%, P<0.05). Myocardial TG content was negatively correlated with EDV (r = −0.47), ESV (r = −0.64), LV mass (r = −0.44), and epicardial fat volume (r = 0.47) (all P<0.05). In conclusion, lower levels of myocardial TG content were observed in endurance athletes and were associated with morphological changes related to physiological LV alteration in athletes, suggesting that metabolic imaging for measurement of myocardial TG content by 1H-MRS may be a useful technique for noninvasively assessing the “athlete’s heart”.

Increased circulating soluble LR11 in patients with acute coronary syndrome.

BACKGROUND LR11 (also so called SorLA or SORL1) is a novel marker of intimal smooth muscle cell (SMC) proliferation. Vascular SMCs play important roles in the development of atherosclerosis interacting with macrophages in a vulnerable plaque of patients with acute coronary syndrome (ACS).The present study determines whether soluble LR11 (sLR11) is associated with ACS. METHODS We studied 100 patients with coronary artery disease (CAD) comprising 50 consecutive patients with acute coronary syndrome (ACS; mean age 62.3±13.0 years; male 78.0%) who were successfully treated with percutaneous coronary intervention and 50 age- and sex-matched stable angina pectoris (SAP) patients as control. Concentration of sLR11 was measured by sandwich enzyme-linked immunosorbent assay method. RESULTS Circulating sLR11 was significantly increased in patients with ACS compared with SAP (9.88±2.78 vs. 8.18±1.11 ng/ml, p<0.01). Multivariate logistic regression analysis indicated that sLR11 was independently associated with ACS (odds ratio (OR), sLR11 quartile increment, 2.18, 95% confidence interval (CI) 1.21-4.19, p<0.01). Among various biomarkers of acute coronary syndrome, hsCRP were significantly correlated with LR11 (r=0.480, p<0.01). CONCLUSIONS There is a statistical significant association between LR11 and ACS and may be a useful biomarker for the development of acute coronary syndrome.

Circulating soluble LR11, a novel marker of smooth muscle cell proliferation, is enhanced after coronary stenting in response to vascular injury

OBJECTIVE Restenosis after vascular intervention remains a major clinical problem. Circulating LR11 has been shown a novel marker of intimal smooth muscle cell (SMC) proliferation in human and animal studies. The present study was performed to clarify the clinical significance of circulating LR11 in patients with stable angina pectoris after coronary stenting. METHODS AND RESULTS We firstly investigated the circulating sLR11 levels for 28 days after arterial injury in mice, and then assessed time-dependent change in circulating sLR11 level after coronary stenting in a clinical study. Mouse sLR11 levels rapidly increased to 4.0-fold of the control value without cuff placement at postoperative day (POD) 14, and the levels gradually declined to 3.1-fold of the control value until POD 28 in mice. The circulating soluble LR11 levels were measured (before and at 14, 60 and 240 days after coronary stenting in a clinical study of 102 consecutive patients with stable angina pectoris who were treated with percutaneous coronary intervention. Circulating sLR11 levels were significantly increased on days 14 and 60 after the procedure and positively associated with the angiographic late loss index. CONCLUSIONS Our study suggested that circulating sLR11 levels may be a potential marker for angiographic late loss in patients after coronary stenting. Further mechanistic studies are expected to know the clinical significance of sLR11 as a novel marker for intimal SMC.

Prognostic significance of glomerular filtration rate estimated by the Japanese equation among patients who underwent complete coronary revascularization.

An equation that accurately estimates the glomerular filtration rate (GFR) in the Japanese population has been proposed; however, the prognostic significance of estimated GFR (eGFR) defined according to this equation has not been reported. In addition, the prognostic significance of eGFR during long-term follow-up after complete coronary revascularization remains unclear. We assessed the prognostic significance of eGFR values, estimated by the new Japanese equation, in a cohort of patients following complete coronary revascularization. We studied consecutive patients with complete revascularization from 1984 to 1992. Patients on dialysis were excluded. A novel Japanese equation was used to estimate the GFR: eGFR=194 × (serum creatinine)−1.094 × (age)−0.287 ( × 0.739 if female). Multivariate Cox proportional hazards regression analyses were performed to determine all-cause and cardiac mortality. We analyzed data of 1809 patients, of whom 571 (31.6%) had an eGFR of ⩾90 ml min−1 per 1.73 m2, 917 (50.7%) had an eGFR of 60–89 ml min−1 per 1.73 m2, 298 (16.5%) had an eGFR of 30–59 ml min−1 per 1.73 m2 and 23 (1.3%) had an eGFR of <30 ml min−1 per 1.73 m2. During follow-up (11.4±2.9 years), there were 397 (22.0%) all-cause and 123 (6.8%) cardiac deaths overall. Patients with an eGFR of 30–59 ml min−1 per 1.73 m2, and <30 ml min−1 per 1.73 m2 revealed significantly greater risk of all-cause mortality than those with eGFR of ⩾90 ml min−1 per 1.73 m2 (hazard ratio (HR) 1.91, P<0.001, HR 3.35, P<0.001, respectively). Furthermore, incidence of cardiac death was higher in patients with an eGFR of 30–59 ml min−1 per 1.73 m2 than those with an eGFR of ⩾90 ml min−1 per 1.73 m2 (HR 2.89, P<0.001). GFR as estimated using the new Japanese equation had a prognostic significance among patients with complete coronary revascularization.

Evaluation of myocardial triglyceride accumulation assessed on 1H-magnetic resonance spectroscopy in apparently healthy Japanese subjects.

OBJECTIVE Proton magnetic resonance spectroscopy ((1)H-MRS) enables the clinician to noninvasively assess the amount of ectopic fat in the liver, skeletal muscle and myocardium. Recent studies have reported that the myocardial triglyceride (TG) content is associated with aging, metabolic disorders and cardiac dysfunction. However, the clinical usefulness of myocardial TG measurements in Japanese subjects has not been fully investigated. METHODS The myocardial TG content was evaluated using (1)H-MRS in 37 apparently healthy Japanese subjects, and the left ventricular function was measured on cardiac magnetic resonance imaging (MRI). Blood pressure, body composition and biochemical markers were measured in a fasting state, and cardiopulmonary exercise testing (CPX) was performed to evaluate exercise capacity. RESULTS The mean myocardial TG content was 0.85±0.40%. The myocardial TG content was significantly associated with the percent body fat (r=0.39), serum triglyceride level (r=0.40), estimated glomerular filtration rate (r=-0.37), anaerobic threshold (r=-0.36), maximal load of CPX (r=0.39), left ventricular end-diastolic volume (r=-0.41) and left ventricular end-systolic volume (LVESV) (r=-0.51) (all: p<0.05). In a multivariate analysis, the LVESV was found to be an independent factor of the myocardial TG content. CONCLUSION (1)H-MRS may be useful for assessing the associations between the myocardial TG content and various clinical parameters, including those reflecting obesity, metabolic disorders, cardiac morphology and exercise capacity, noninvasively, even in Japanese subjects.