Journal of Atherosclerosis and Thrombosis
Online ISSN : 1880-3873
Print ISSN : 1340-3478
ISSN-L : 1340-3478
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Review
  • Shizuya Yamashita, Daisaku Masuda, Yuji Matsuzawa
    Type: review-article
    2019 Volume 26 Issue 5 Pages 389-402
    Published: May 01, 2019
    Released: May 01, 2019
    [Advance publication] Released: March 30, 2019
    JOURNALS FREE ACCESS

    Fasting and postprandial hypertriglyceridemia is a risk factor for atherosclerotic cardiovascular diseases (ASCVD). Fibrates have been used to treat dyslipidemia, particularly hypertriglyceridemia, and low HDL-cholesterol (HDL-C). However, conventional fibrates have low selectivity for peroxisome proliferator-activated receptor (PPAR)α. Fibrates’ clinical use causes side effects such as worsening liver function and elevating the creatinine level. Large-scale clinical trials of fibrates have shown negative results for prevention of ASCVD. To overcome these issues, the concept of the selective PPARα modulator (SPPARMα), with a superior balance of efficacy and safety, has been proposed. A SPPARMα, pemafibrate (K-877), was synthesized by Kowa Company, Ltd. for better efficacy and safety. Clinical trials conducted in Japan confirmed the superior effects of pemafibrate on triglyceride reduction and HDL-C elevation.

    Conventional fibrates showed elevated liver function test values and worsened kidney function test values, while pemafibrate demonstrated improved liver function test values and was less likely to increase serum creatinine or decrease the estimated glomerular filtration rate. There were extremely few drug interactions even when it was used concomitantly with various statins. Furthermore, unlike many of the conventional fibrates that are renal excretory-type drugs, pemafibrate is excreted into the bile, so it can be safely used even in patients with impaired renal function and there is no increase in its blood concentration.

    This novel SPPARMα, pemafibrate, has superior benefit-risk balance compared to conventional fibrates and can be used for patients for whom it was difficult to use existing fibrates, including those who are taking statins and those with renal dysfunction. A large-scale trial PROMINENT using pemafibrate for patients with type 2 diabetes is in progress. In the current review, the latest data on pemafibrate will be summarized.

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Editorial
Original Article
  • Kouji Kajinami, Asuka Ozaki, Yuki Tajima, Shizuya Yamashita, Hidenori ...
    Type: Original Article
    2019 Volume 26 Issue 5 Pages 408-431
    Published: May 01, 2019
    Released: May 01, 2019
    [Advance publication] Released: October 26, 2018
    JOURNALS FREE ACCESS

    Aim: Statins are generally well-tolerated but some patients develop adverse events and down-titrate or discontinue statins. It is important to understand the frequency of dyslipidemia patients with the inability to continue statins. The aim of the present study was to identify the frequency of high-risk dyslipidemia patients who are unable to take or not taking statins for any reason using Japanese hospital claims database.

    Methods: 2,527,405 dyslipidemia patients with atherosclerotic cardiovascular disease were investigated between April 2008 and September 2017. Definition 1 included statin discontinuation or down-titration with non-statin lipid modifying therapy (LMT) prescription, rhabdomyolysis or muscle-related symptoms with statin down-titration or discontinuation, or prescription for ≥3 statin types. Definition 2 included all components of Definition 1 in addition to statin down-titration or discontinuation for any reason. Patients never given statins but who started non-statin LMT were considered as Definition 3. The achievement rate of the target LDL-C level was investigated.

    Results: Among 54,296 patients with statin prescription, 2.32% and 48.38% patients were identified as Definition 1 and 2, respectively. Of eligible patients, 13.16% patients were identified as Definition 3. The achievement rate of target LDL-C level was lower in patients meeting each definition than not satisfying each definition.

    Conclusions: There is a proportion of high-risk dyslipidemia patients unable to take or not taking statins for any reason, and it is associated with lower achievement rates of target LDL-C levels. Suboptimal management of LDL-C is directly associated with residual cardiovascular risk and implementation of alternative therapeutic options in addition to existing LMT is warranted.

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  • Kazuo Kitagawa, Naohisa Hosomi, Yoji Nagai, Tatsuo Kagimura, Toshiho O ...
    Type: Original Article
    2019 Volume 26 Issue 5 Pages 432-441
    Published: May 01, 2019
    Released: May 01, 2019
    [Advance publication] Released: October 15, 2018
    JOURNALS FREE ACCESS

    Aims: To investigate the relative contribution of on-treatment low-density lipoprotein (LDL) cholesterol and C-reactive protein (CRP) to the risk of recurrent stroke and transient ischemic attack (TIA) in patients with history of ischemic stroke.

    Methods: A total of 1095 patients with non-cardioembolic ischemic stroke were randomized into two groups: control and patients receiving 10 mg of pravastatin per day. After excluding 18 patients who did not have baseline CRP data, the effects of LDL cholesterol and CRP on recurrent stroke and TIA were prospectively assessed in 1077 patients.

    Results: During the follow-up of 4.9±1.4 years, there were 131 recurrent stroke or TIA cases. Patients with ontreatment LDL cholesterol <120 mg/dL showed 29% reduction in recurrent stroke and TIA than those with LDL cholesterol ≥ 120 mg/dL (event rate 2.20 vs. 3.11 per 100 person-years, hazard ratio [HR] 0.71, 95% confidence interval (CI) 0.50–0.99, p=0.048). Patients with CRP <1 mg/L had 32% reduction compared with that of patients with CRP ≥ 1 mg/L (event rate 2.26 vs. 3.40 per 100 person-years; HR 0.68, 95% CI 0.48–0.96, p=0.031). Although LDL cholesterol and CRP levels were not correlated in individual patients, those who achieved both LDL cholesterol <120 mg/dL and CRP <1 mg/L showed 51% reduction compared with that of patients with LDL cholesterol ≥ 120 mg/dL and CRP ≥ 1 mg/L (event rate 2.02 vs. 4.19 per 100 person-years; HR 0.49, 95% CI 0.31–0.79).

    Conclusions: The control of both LDL cholesterol and CRP levels appears to be effective for preventing recurrent stroke and TIA in patients with non-cardiogenic ischemic stroke.

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  • Kenji Sakata, Tadatsugu Gamou, Hayato Tada, Kenshi Hayashi, Hidekazu I ...
    Type: Original Article
    2019 Volume 26 Issue 5 Pages 442-451
    Published: May 01, 2019
    Released: May 01, 2019
    [Advance publication] Released: September 21, 2018
    JOURNALS FREE ACCESS

    Aim: The prospective, randomized, multicenter Myocardial Ischemia Treated with Percutaneous Coronary Intervention and Plaque Regression by Lipid Lowering & Blood Pressure Controlling assessed by Intravascular Ultrasonography (MILLION) study demonstrated that combined treatment with atorvastatin and amlodipine enhanced coronary artery plaque regression. Although the baseline high-sensitive C-reactive protein (hs-CRP) reportedly plays an important role in atherogenesis, few data exist regarding the relationship between hs-CRP and plaque regression in patients receiving a combined atorvastatin and amlodipine therapy.

    Methods: A total of 68 patients (male, 55; mean age, 64.2 years) with baseline and follow-up 3-dimensional intravascular ultrasound examinations in the MILLION study were stratified by baseline hs-CRP level quartiles. The serial measurements of lipid, blood pressure, and percentage changes in the plaque volume were compared between the groups, and the factors associated with the percentage change in the plaque volume were assessed.

    Results: There were no significant between-group differences in the extent of change in low-density lipoprotein cholesterol (LDL-C) or systolic and diastolic blood pressure after 18–24 months of treatment. The percentage change in the plaque volume showed a linear association with the baseline hs-CRP (p for trend <0.05); however, there was no correlation with changes in LDL-C or systolic and diastolic blood pressure. In the multiple regression analysis, the baseline hs-CRP level was independently associated with the percentage change in the plaque volume (β=0.29, p=0.022).

    Conclusions: Coronary plaque regression was associated with the baseline hs-CRP level in patients treated with a combined lipid- and blood pressure-lowering therapy.

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  • Cecilia Kimani, Aya Kadota, Katsuyuki Miura, Akira Fujiyoshi, Maryam Z ...
    Type: Original Article
    2019 Volume 26 Issue 5 Pages 452-464
    Published: May 01, 2019
    Released: May 01, 2019
    [Advance publication] Released: November 01, 2018
    JOURNALS FREE ACCESS

    Aims: Calcification in the coronary and aortic arteries has been linked to cardiovascular morbidity and mortality. The pathophysiological influence of aortic artery calcification (AAC) differs from that of coronary artery calcification (CAC). We aimed to compare the relationships between CAC and AAC and cardiovascular disease (CVD) risk factors.

    Methods: We examined a random sample of 1035 Japanese men aged 40–79 years. CAC and AAC were measured by computed tomography and scored according to the Agatston method. Using a logistic regression, we calculated the odds ratio (OR) as being in the highest quintile (Q5) of the calcification score compared to the lower quintiles (Q1–Q4) per 1 standard deviation higher CVD risk factor. Models were simultaneously adjusted for age, body mass index (BMI), systolic blood pressure, smoking (pack-year), alcohol intake, hemoglobin A1c, uric acid, estimated glomerular filtration rate (eGFR), serum lipids, and C-reactive protein. Differences in ORs were investigated using a generalized estimating equation. We performed a multiple linear regression using log-transformed CAC and AAC values as dependent variables.

    Results: CAC and AAC were independently associated with age (OR, 95% CI: 2.30 [1.77–2.98] for CAC and 3.48 [2.57–4.73] for AAC), p for difference <0.001), systolic blood pressure (1.29 [1.08–1.53] and 1.28 [1.07–1.54], p for difference=0.270), and smoking (1.22, [1.04–1.43] and 1.34 [1.13–1.58]) p for difference=0.071). Alcohol correlated with AAC only (1.17 [0.97–1.41] for CAC and 1.42 [1.16–1.73] for AAC, p for difference= 0.020).

    Conclusions: CAC and AAC were associated with similar CVD risk factors. The strength of association slightly differed between CAC and AAC.

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  • Koji Takahashi, Tomoyuki Yamamoto, Shinichi Tsuda, Fumio Okabe, Tadash ...
    Type: Original Article
    2019 Volume 26 Issue 5 Pages 465-475
    Published: May 01, 2019
    Released: May 01, 2019
    [Advance publication] Released: December 04, 2018
    JOURNALS FREE ACCESS

    Aim: The Cardio-Ankle Vascular Index (CAVI) is a stiffness index of the arterial tree from the origin of the aorta to the ankle, independent of blood pressure at the time of measurement. The CAVI equation includes the coefficients “a” and “b” to adjust it to the value of Hasegawa’s pulse wave velocity, which is compensated for at 80 mmHg of diastolic pressure. To verify this adjustment with the coefficients, the clinical significance of CAVI and CAVI without the coefficients (haβ) were compared in both an epidemiological study and an acute clinical study.

    Methods: In the epidemiological study, the significances of CAVI and haβ among people with or without coronary risks such as hypertension, dyslipidemia, hyperglycemia, and abnormal electrocardiography change, were compared. In the acute clinical study, nitroglycerin was administered to subjects in a control group and to coronary artery disease patients, observing CAVI and haβ values over a 20-min period.

    Results: There was no discrepancy in terms of statistically significant differences between CAVI and haβ among subjects with or without risk factors. Furthermore, there was also no discrepancy in terms of statistically significant differences between CAVI and haβ during the changes of those values following nitroglycerin administration over a 20-min period.

    Conclusion: In both the epidemiologic and clinical studies, there was no discrepancy in terms of significant differences between CAVI and haβ. These results suggest that both are valid as indices of stiffness of the arterial tree from the origin of the aorta to the ankle.

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  • Hiroko Iino, Tomoko Okano, Masao Daimon, Kazuno Sasaki, Mayumi Chigira ...
    Type: Original Article
    2019 Volume 26 Issue 5 Pages 476-487
    Published: May 01, 2019
    Released: May 01, 2019
    [Advance publication] Released: October 20, 2018
    JOURNALS FREE ACCESS

    Aim: We investigated the clinical usefulness of carotid arterial strain and the strain rate for evaluating the progression of arteriosclerosis measured using a two-dimensional speckle-tracking method in carotid ultrasonography.

    Methods: We enrolled 259 participants (age: 64±12 years; men: 149; women: 110) in this retrospective analysis. The circumferential strain and the strain rate were measured in bilateral common carotid arteries, and the lowest values were used for the analyses. To assess the characteristics of strain and the strain rate, we investigated the associations between the strain values and gender, age, body mass index (BMI), blood pressure (BP), and the presence of hypertension, diabetes mellitus, and hyperlipidemia. We also examined the explanatory factors for the strain values using clinical parameters along with the intima-media thickness (IMT), the ankle brachial index (ABI), and the cardio-ankle vascular index (CAVI) as possible candidates. Finally, we investigated whether the strain values might be an independent predictor for vascular diseases using multivariate logistic regression analyses.

    Results: The carotid circumferential strain and the strain rate were significantly correlated with age, IMT, and the CAVI, but not with the BMI, BP, or ABI. Strain and the strain rates were lower in participants with hypertension or cerebrovascular disease and were selected as significant predictive factors for the presence of cerebrovascular diseases, together with diabetes and the CAVI.

    Conclusions: Strain and the strain rate of carotid arteries, which could represent local arterial stiffness, might be associated with atherosclerosis and could possibly be used to predict cerebrovascular disease.

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  • Yutaka Igarashi, Nobuhiko Akazawa, Seiji Maeda
    Type: Original Article
    2019 Volume 26 Issue 5 Pages 488-503
    Published: May 01, 2019
    Released: May 01, 2019
    [Advance publication] Released: October 31, 2018
    JOURNALS FREE ACCESS

    Aim: The purpose of the current work was to review the effects of regular aerobic exercise on serum lipid and lipoprotein levels in East Asians using meta-analysis.

    Methods: The randomized controlled trials analyzed involved healthy adults who were East Asians with a mean age ≥40 years, an exercise group that only performed regular aerobic exercise, and a control group that did not carry out exercise-related intervention; the trials indicated mean high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), or triglyceride (TG). The mean difference (MD) was defined as the difference (mean value at post-intervention in the exercise group-mean value at baseline in the exercise group)-(mean value at post-intervention in the control group-mean value at baseline in the control group) in HDL-C, LDL-C, TC, and TG and was calculated for each trial. The weighted MD was calculated with a random-effects model.

    Results: The meta-analysis examined 994 subjects in 25 studies. The weighted MD in HDL-C, TC, and TG improved significantly (HDL-C, 2.2 mg/dL; TC, -5.8 mg/dL; TG, -13.7 mg/dL). The weighted MD in HDL-C and TC contained significant heterogeneity (HDL-C, I2=45.1%; TC, I2=56.2%). When trials were limited to those involving moderate-intensity exercise (55%–69% of the maximum heart rate) or an exercise volume ≥150 min/week, the weighted MD in HDL-C, LDL-C, TC, and TG improved significantly and did not contain significant heterogeneity.

    Conclusions: The findings suggest that the ideal form of exercise to improve lipid and lipoprotein levels in East Asians is exercise of moderate-intensity and in a volume ≥150 min/week.

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