Journal of Atherosclerosis and Thrombosis
Online ISSN : 1880-3873
Print ISSN : 1340-3478
ISSN-L : 1340-3478
Current issue
Displaying 1-22 of 22 articles from this issue
Review
  • Shinya Goto, Darren K. McGuire, Shinichi Goto
    Subject area: Review
    2022 Volume 29 Issue 5 Pages 559-562
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
    Advance online publication: October 02, 2021
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    Advances in High-performance computing (HPC) technology have reached the capacity to inform cardiovascular (CV) science in the realm of both inductive and constructive approaches. Clinical trials allow for the comparison of the effect of an intervention without the need to understand the mechanism. This is a typical example of an inductive approach. In the HPC field, training an artificial intelligence (AI) model, constructed by neural networks, to predict future CV events with the use of large scale multi-dimensional datasets is the counterpart that may rely on as well as inform understanding of mechanistic underpinnings for optimization. However, in contrast to clinical trials, AI can calculate event risk at the individual level and has the potential to inform and refine the application of personalized medicine.

    Despite this clear strength, results from AI analyses may identify otherwise unidentified/unexpected (i.e. non-intuitive) relationships between multi-dimensional data and clinical outcomes that may further unravel potential mechanistic pathways and identify potential therapeutic targets, therebycontributing to the parsing of observational associations from causal links. The constructive approach will remain critical to overcome limitations of existing knowledge and anchored biases to actualize a more sophisticated understanding of the complex pathobiology of CV diseases.

    HPC technology has the potential to underpin this constructive approach in CV basic and clinical science. In general, even complex biological phenomena can be reduced to combinations of simple biological/chemical/physical laws. In the deductive approach, the focus/intent is to explain complex CV diseases by combinations of simple principles.

Editorial
Original Article
  • Pingting Zhong, Jie Qin, Zhixi Li, Lei Jiang, Qingsheng Peng, Manqing ...
    Subject area: Original Article
    2022 Volume 29 Issue 5 Pages 579-596
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
    Advance online publication: March 19, 2021
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    Aims: To develop and validate a nomogram using retinal vasculature features and clinical variables to predict coronary artery disease (CAD) in patients with suspected angina.

    Methods: The prediction model consisting of 795 participants was developed in a training set of 508 participants with suspected angina due to CAD, and data were collected from January 2018 to June 2019. The held-out validation was conducted with 287 consecutive patients from July 2019 to November 2019. All patients with suspected CAD received optical coherence tomography angiography (OCTA) examination before undergoing coronary CT angiography. LASSO regression model was used for data reduction and feature selection. Multivariable logistic regression analysis was used to develop the retinal vasculature model for predicting the probability of the presence of CAD.

    Results: Three potential OCTA parameters including vessel density of the nasal and temporal perifovea in the superficial capillary plexus and vessel density of the inferior parafovea in the deep capillary plexus were further selected as independent retinal vasculature predictors. Model clinical electrocardiogram (ECG) OCTA (clinical variables+ECG+OCTA) was presented as the individual prediction nomogram, with good discrimination (AUC of 0.942 [95% CI, 0.923–0.961] and 0.897 [95% CI, 0.861–0.933] in the training and held-out validation sets, respectively) and good calibration. Decision curve analysis indicated the clinical applicability of this retinal vasculature nomogram.

    Conclusions: The presented retinal vasculature nomogram based on individual probability can accurately identify the presence of CAD, which could improve patient selection and diagnostic yield of aggressive testing before determining a diagnosis.

  • Tetsuji Morishita, Daisuke Takada, Jung-ho Shin, Takuya Higuchi, Susum ...
    Subject area: Original Article
    2022 Volume 29 Issue 5 Pages 597-607
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
    Advance online publication: April 01, 2021
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    Aim: The coronavirus disease 2019 (COVID-19) pandemic has left negative spillover effects on the entire health care system. Previous studies have suggested significant declines in cases of acute coronary syndrome (ACS) and primary percutaneous coronary intervention (PCI) during the COVID-19 pandemic.

    Methods: We performed a quasi-experimental, retrospective cohort study of ACS hospitalisations by using a multi-institutional administrative claims database in Japan. We used interrupted time series analyses to ascertain impacts on cases, treatment approaches, and in-hospital mortality before and after Japan’s state of emergency to respond to COVID-19. The primary outcome was the change in ACS cases per week.

    Results: A total of 30,198 ACS cases (including 21,612 acute myocardial infarction and 8,586 unstable angina) were confirmed between 1st July 2018 and 30th June 2020. After the state of emergency, an immediate decrease was observed in ACS cases per week (-18.3%; 95% confidence interval, -13.1 to -23.5%). No significant differences were found in the severity of Killip classification (P=0.51) or cases of fibrinolytic therapy (P=0.74). The impact of the COVID-19 pandemic on in-hospital mortality in ACS patients was no longer observed after adjustment for clinical characteristics (adjusted odds ratio, 0.93; 95% confidence interval, 0.78 to 1.12; P=0.49).

    Conclusions: We demonstrated the characteristics and trends of ACS cases in a Japanese population by applying interrupted time series analyses. Our findings provide significant insights into the association between COVID-19 and decreases in ACS hospitalisations during the pandemic.

  • Shizuya Yamashita, Daisaku Masuda, Mariko Harada-Shiba, Hidenori Arai, ...
    Subject area: Original Article
    2022 Volume 29 Issue 5 Pages 608-638
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
    Advance online publication: May 13, 2021
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    Aims: Familial hypercholesterolemia (FH) is a genetic disorder characterized by high serum levels of low-density lipoprotein (LDL)-cholesterol (LDL-C), tendon and skin xanthomas, and premature coronary artery disease (CAD). In Japan, detailed information on the current status of drug therapies for patients with FH has not been reported so far, and their efficacy and safety have not been clarified. After the introduction of ezetimibe, which can further reduce serum LDL-C levels on top of statins, the changes of management for FH patients with these drugs are of particular interest. The current study aimed to evaluate the clinical status of FH heterozygotes and homozygotes, especially focusing on the real-world lipid-lowering drug therapy, attained serum LDL-C levels, and cardiovascular events at registration and during the follow-up.

    Methods: The FAME Study enrolled 762 heterozygous (including 17 newly diagnosed cases) and 7 homozygous FH patients from hospitals and clinics nationwide. Diagnosis of FH was based upon the criteria defined in the Study Report in 2008 of the Research Committee on Primary Hyperlipidemia supported by Grants-in-Aid for Scientific Research from the Japanese Ministry of Health, Labor and Welfare. Data analysis was primarily carried on heterozygous FH patients.

    Results: Xanthoma or thickening of the Achilles tendon was observed in more than 80% of the patients. CAD was recorded in 23% of patients. Patients with parental and sibling CAD accounted for 47% and 24%, respectively. At baseline, patients without CAD who had LDL-C <100 mg/dL accounted for 12.3% and those with CAD who had attained the target (LDL-C <70 mg/dL) in the secondary prevention accounted for only 1.8%. In the multiple logistic analysis, male sex, age >40, heterozygous FH score >20, hypertension, and sibling CAD were significantly and positively associated with prevalent CAD, whereas serum HDL-cholesterol levels showed a significant inverse association with CAD. Patients treated with statin alone, statin+ezetimibe, statin+resin, or statin+probucol accounted for 31.1%, 26.3%, 4.0%, and 3.7%, respectively. Patients treated with three-drug combination (statin+ezetimibe+resin or statin+ezetimibe+probucol) accounted for 7.5%. Statins and ezetimibe were used in 88.0% and 48.0% at the baseline, respectively. Although high-intensity statins were mainly prescribed, statin doses were much lower than those reported in Western countries. The addition of ezetimibe resulted in ~20% reduction in serum LDL-C. CAD was diagnosed in 17 patients with 21 episodes during follow-up. The Cox hazard model analysis demonstrated that male sex, CAD at the baseline, and parental CAD were related to the development of atherosclerotic cardiovascular disease (ASCVD) events. Furthermore, an increase in serum HDL-C was associated with a significant reduction of ASCVD events, while serum LDL-C and triglyceride levels were not related to ASCVD events.

    Conclusion: The prevalence of CAD in Japanese patients with heterozygous FH is still very high. In most of the cases, the target level of serum LDL-C was not achieved for primary and secondary prevention of CAD, suggesting that a more aggressive LDL-C lowering and appropriate management of residual risks are necessary.

  • Chin-Chou Huang, Dau-Ming Niu, Min-Ji Charng
    Subject area: Original Article
    2022 Volume 29 Issue 5 Pages 639-653
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
    Advance online publication: May 16, 2021
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    Aim: Familial hypercholesterolemia (FH) is underdiagnosed in most countries. The genetic heterogeneity of FH requires an algorithm to efficiently integrate genetic testing into clinical practice. We aimed to report the spectrum of genetic mutations from patients with clinically diagnosed FH in Taiwan.

    Methods: Patients with LDL-C>190 mg/dL or those with probable or definite FH according to the Taiwan Lipid Guidelines underwent genetic testing. Samples from 750 index patients from the Taiwan FH registry were screened using custom-made mass spectrometry, followed by targeted next generation sequencing (NGS) and/or multiplex ligation-dependent probe amplification (MLPA) if found negative.

    Results: The mean age of the patients was 52.4±15.1 years and 40.9% were male. Mutations were detected in 445 patients (59.3%). The distribution of mutations was as follows: LDLR (n=395), APOB (n=58), PCSK9 (n=0), and ABCG5 (n=3). The most common mutations were APOB c.10579 C>T (p.R3527W) (12.6%), LDLR c.986 G>A (p.C329Y) (11.5%), and LDLR c.1747 C>T (p.H583Y) (10.8%). LDLR c.1187-10 G>A (IVS 8-10) and APOB c.10580 G>A (p.R3527Q) were detected using targeted NGS in Taiwan for the first time. Four novel mutations were identified, including LDLR c.1060+2 T>C (IVS 7+2), LDLR c.1139 A>C (p.E380A), LDLR c.1322 T>C (p.A431T)+c.1867 A>G (p.I623V), and ABCG5 c.1337 G>A (p.R447Q).

    Conclusion: LDLR and APOB, but not PCSK9, mutations were the major genetic causes of FH. Four novel mutations in LDLR or ABCG5 were identified. This genetic screening method using mass spectrometry, targeted NGS, and MLPA analysis provided an efficient algorithm for genetic testing for clinically diagnosed FH in Taiwan.

  • Nobuo Sasaki, Ryo Maeda, Ryoji Ozono, Yukiko Nakano, Yukihito Higashi
    Subject area: Original Article
    2022 Volume 29 Issue 5 Pages 654-666
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
    Advance online publication: May 19, 2021
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    Aim: Diameter, intima–media thickness (IMT), and flow parameters, including resistance index (RI) and pulsatility index (PI), in the common carotid artery (CCA) are markers of arterial remodeling, atherosclerosis, and vascular resistance, respectively. We investigated the differences among these markers in association with plasma glucose level, serum insulin level, and insulin resistance in participants without cardiovascular disease.

    Methods: CCA parameters (including the CCA interadventitial diameter and mean IMT at the time of 75-g oral glucose tolerance testing) were assessed in 4218 participants. RI and PI were assessed in 3380 of these participants. To assess plasma glucose and serum immunoreactive insulin profiles during oral glucose tolerance testing, we used the total areas under the curves (AUCglu and AUCins, respectively). We used the homeostasis model assessment of insulin resistance (HOMA-IR) and the Matsuda index to assess insulin resistance. Insulin secretion was assessed with the HOMA-β.

    Results: AUCglu was significantly associated with CCA interadventitial diameter (β=0.048, P<0.001), RI (β=0.144, P<0.001), and PI (β=0.103, P<0.001) but not with mean IMT. AUCins (β=−0.064, P<0.001) and HOMA-β (β=−0.054, P<0.001) were significantly and negatively associated with CCA interadventitial diameter, but not with mean IMT. Both HOMA-IR and Matsuda index were significantly associated with RI and PI.

    Conclusions: These findings indicate that all CCA parameters except IMT are associated with impaired glucose metabolism in patients without cardiovascular disease.

  • Keiko Nagahara, Tsuyoshi Nishibukuro, Yasuko Ogiwara, Kento Ikegawa, H ...
    Subject area: Original Article
    2022 Volume 29 Issue 5 Pages 667-677
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
    Advance online publication: May 20, 2021
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    Aim: This study aimed to elucidate the gene and lipid profiles of children clinically diagnosed with familial hypercholesterolemia (FH).

    Methods: A total of 21 dyslipidemia-related Mendelian genes, including FH causative genes (LDLR, APOB, and PCSK9) and LDL-altering genes (APOE, LDLRAP1, and ABCG5/8), were sequenced in 33 Japanese children (mean age, 9.7±4.2 years) with FH from 29 families.

    Results: Fifteen children (45.5%) with pathogenic variants in LDLR (eight different heterozygous variants) and one child (3.0%) with the PCSK9 variant were found. Among 17 patients without FH causative gene variants, 3 children had variants in LDL-altering genes, an APOE variant and two ABCG8 variants. The mean serum total cholesterol (280 vs 246 mg/dL), LDL-cholesterol (LDL-C, 217 vs 177 mg/dL), and non-HDL cholesterol (228 vs 188 mg/dL) levels were significantly higher in the pathogenic variant-positive group than in the variant-negative group. In the variant-positive group, 81.3% of patients had LDL-C levels ≥ 180 mg/dL but 35.3% in the variant-negative group. The mean LDL-C level was significantly lower in children with missense variants, especially with the p.Leu568Val variant, than in children with other variants in LDLR, whereas the LDL-altering variants had similar effects on the increase in serum LDL-C to LDLR p.Leu568Val.

    Conclusion: Approximately half of the children clinically diagnosed with FH had pathogenic variants in FH causative genes. The serum LDL-C levels tend to be high in FH children with pathogenic variations, and the levels are by the types of variants. Genetic analysis is useful; however, further study on FH without any variants is required.

  • Atsuko Nakayama, Hiroyuki Morita, Tatsuyuki Sato, Takuya Kawahara, Nor ...
    Subject area: Original Article
    2022 Volume 29 Issue 5 Pages 678-691
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
    Advance online publication: May 14, 2021
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    Aim: We explored the superiority of small dense low-density lipoprotein cholesterol (sdLDL-C) as a marker for predicting not only the occurrence of cardiovascular (CV) events but also the need for laser treatment in patients with hypercholesterolemia and diabetic retinopathy.

    Methods: We performed a sub-analysis of the intEnsive statin therapy for hyper-cholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY) study (n=5042), in which patients were assigned randomly to intensive or standard statin therapy targeting low-density lipoprotein cholesterol <70 mg/dl or 100-120 mg/dl. Using the survival analysis, the risks for CV events and the need for laser treatment were evaluated according to the lipids one year after registration.

    Results: The patients were 63±11 years old. LDL-C and sdLDL-C levels were 98±25 and 32±14 mg/dl, respectively, one year after registration. The sdLDL-C level had a strong positive correlation with apolipoprotein B level (r=0.83 at registration). SdLDL-C was a sensitive marker for predicting CV events when comparing among the quartiles according to sdLDL-C levels (hazard ratios: HR for quartiles 1-4 were 1.0, 1.4, 1.6, and 2.5, respectively; p for trend <0.01). Also, sdLDL-C was a sensitive marker for predicting the need for laser treatment among lipids (log rank, p=0.009), especially in patients with elderly (≧65 yrs) and obesity (BMI ≧25 kg/m2).

    Conclusions: SdLDL-C is a sensitive target marker to predict cardiovascular events as well as the need for laser treatment in patients with hypercholesterolemia and diabetic retinopathy.

  • Daisuke Fujioka, Yosuke Watanabe, Takamitsu Nakamura, Takashi Yokoyama ...
    Subject area: Original Article
    2022 Volume 29 Issue 5 Pages 692-718
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
    Advance online publication: March 27, 2021
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    Aims: It was suggested that group V secretory phospholipase A2 (sPLA2-V) existed in the nucleus. This study examined whether nuclear sPLA2-V plays a role in endocytosis of acetylated low-density lipoprotein (AcLDL) in monocyte/macrophage-like cell line RAW264.7 cells.

    Methods: RAW264.7 cells were transfected with shRNA vector targeting sPLA2-V (sPLA2-V-knockdown [KD] cells) or empty vector (sPLA2-V-wild-type [WT] cells). AcLDL endocytosis was assessed by incubation with 125I-AcLDL or AcLDL conjugated with pHrodo. Actin polymerization was assessed by flow cytometry using Alexa Fluor 546-phalloidin.

    Results: In immunofluorescence microscopic studies, sPLA2-V was detected in the nucleus. ChIP-Seq and ChIP-qPCR analyses showed binding of sPLA2-V to the promoter region of the phosphoglycerate kinase 1 (Pgk1) gene. In the promoter assay, sPLA2-V-KD cells had lower promoter activity of the Pgk1 gene than sPLA2-V-WT cells, and this decrease could be reversed by transfection with a vector encoding sPLA2-V-H48Q that lacks enzymatic activity. Compared with sPLA2-V-WT cells, sPLA2-V-KD cells had decreased PGK1 protein expression, beclin 1 (Beclin1) phosphorylation at S30, and class III PI3-kinase activity that could also be restored by transfection with sPLA2-V-H48Q. sPLA2-V-KD cells had impaired actin polymerization and endocytosis, which was reversed by introduction of sPLA2-V-H48Q or PGK1 overexpression. In sPLA2-V-WT cells, siRNA-mediated depletion of PGK1 suppressed Beclin1 phosphorylation and impaired actin polymerization and intracellular trafficking of pHrodo-conjugated AcLDL.

    Conclusions: Nuclear sPLA2-V binds to the Pgk1 gene promoter region and increases its transcriptional activity. sPLA2-V regulates AcLDL endocytosis through PGK1-Beclin1 in a manner that is independent of its enzymatic activity in RAW264.7 cells.

  • Hiroyuki Naito, Tomohisa Nezu, Naohisa Hosomi, Daisuke Kuzume, Shiro A ...
    2022 Volume 29 Issue 5 Pages 719-730
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
    Advance online publication: March 30, 2021
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    Aims: Elevated serum alkaline phosphatase (ALP) levels are associated with an increased risk of cerebrocardiovascular diseases. However, the associations of ALP with peripheral arterial disease (PAD) and outcomes in patients with acute ischemic stroke (AIS) are not well-known.

    Methods: We examined the association between ALP levels and the ankle–brachial index (ABI) in 2111 consecutive patients with AIS. A poor functional outcome was defined as a modified Rankin Scale (mRS) score of 3–6 at 3 months after stroke. A low ABI was defined as a value of ≤ 0.9.

    Results: Of the total cohort, 482 patients (22.8%) had a low ABI. ALP levels were higher in patients with a low ABI than in those without (p<0.001). The multivariable logistic analysis revealed that quartiles of ALP levels were significantly associated with a low ABI (odds ratio [OR]: 1.20, 95% confidence interval [CI]: 1.08–1.33). Of the 1322 patients with a premorbid mRS score of 0–2, 434 patients (32.8%) had a poor outcome. The multivariable analysis revealed that elevated serum ALP levels and a low ABI were independently associated with poor stroke outcomes after adjustment for baseline characteristics (OR: 1.21, 95% CI: 1.07–1.38, and OR: 2.00, 95% CI: 1.40–2.84, respectively).

    Conclusions: Increased serum ALP levels are significantly associated with a low ABI. These indicators are independent prognostic factors for poor stroke outcomes at 3 months.

  • Takuya Matsumoto, Shinichiro Yoshino, Tadashi Furuyama, Koichi Morisak ...
    Subject area: Original Article
    2022 Volume 29 Issue 5 Pages 731-746
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
    Advance online publication: April 28, 2021
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    Aim: To assess the results of a phase I/IIa open-label dose-escalation clinical trial of 5-day repeated intramuscular administration of pitavastatin-incorporated poly (lactic-co-glycolic acid) nanoparticles (NK-104-NP) in patients with chronic limb threatening ischemia (CLTI).

    Methods: NK-104-NP was formulated using an emulsion solvent diffusion method. NK-104-NP at four doses (nanoparticles containing 0.5, 1, 2, and 4 mg of pitavastatin calcium, n=4 patients per dose) was investigated in a dose-escalation manner and administered intramuscularly into the ischemic limbs of 16 patients with CLTI. The safety and therapeutic efficacy of treatment were investigated over a 26-week follow-up period.

    Results: No cardiovascular or other serious adverse events caused by NK-104-NP were detected during the follow-up period. Improvements in Fontaine and Rutherford classifications were noted in five patients (one, three, and one in the 1-, 2-, and 4-mg dose groups, respectively). Pharmacokinetic parameters including the maximum serum concentration and the area under the blood concentration–time curve increased with pitavastatin treatment in a dose-dependent manner. The area under the curve was slightly increased at day 5 compared with that at day 1 of treatment, although the difference was not statistically significant.

    Conclusions: This is the first clinical trial of pitavastatin-incorporated nanoparticles in patients with CLTI. Intramuscular administration of NK-104-NP to the ischemic limbs of patients with CLTI was safe and well tolerated and resulted in improvements in limb function.

  • Senta Gewalt, Shqipdona Lahu, Gjin Ndrepepa, Costanza Pellegrini, Isab ...
    Subject area: Original Article
    2022 Volume 29 Issue 5 Pages 747-761
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
    Advance online publication: April 16, 2021
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    Aim: Sex-specific analyses of direct head-to-head comparisons between newer P2Y12 inhibitors are limited. This study was conducted to assess the efficacy and safety of ticagrelor versus prasugrel in women and men with acute coronary syndromes (ACS) planned for an invasive strategy.

    Methods: This pre-specified analysis of the ISAR-REACT 5 trial included 956 women and 3,062 men with ACS randomly assigned to either ticagrelor or prasugrel. The primary endpoint was the 12-month incidence of death, myocardial infarction, or stroke; the safety endpoint was the 12-month incidence of bleeding (type 3–5 according to the Bleeding Academic Research Consortium [BARC]).

    Results: The primary endpoint occurred in 42 women (8.9%) in the ticagrelor group and 39 women (8.3%) in the prasugrel group (hazard ratio [HR]=1.10, 95% confidence interval [CI] 0.71–1.70, P=0.657) and in 142 men (9.4%) in the ticagrelor group and 98 men (6.5%) in the prasugrel group (HR=1.47 [1.13–1.90], P=0.004; P for interaction [Pint]=0.275). BARC type 3–5 bleeding occurred in 36 women (9.7%) in the ticagrelor group and 34 women (9.7%) in the prasugrel group (HR=1.04 [0.65–1.67], P=0.856) and in 59 men in the ticagrelor group (4.4%) and 46 men (3.6%) in the prasugrel group (HR=1.24 [0.85–1.83], P=0.266; Pint=0.571).

    Conclusions: Although there was no significant interaction between sex and treatment effect of study drugs, the superior efficacy of prasugrel was more evident among men. No difference in bleeding between the two study groups was seen for both women and men.

  • Tsutomu Hirano, Rieko Kodera, Takeshi Hirashima, Natsuko Suzuki, Ema A ...
    Subject area: Original Article
    2022 Volume 29 Issue 5 Pages 762-774
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
    Advance online publication: April 29, 2021
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    Aims: Abnormal compositional changes in low-density lipoprotein (LDL) particles, such as triglyceride (TG) enrichment and size reduction, are common in patients with diabetes. Several cohort studies have demonstrated that LDL-TG and sdLDL-cholesterol (C) are sensitive biomarkers for predicting atherosclerotic cardiovascular diseases beyond LDL-C. Although sdLDL has been extensively studied, little is known about the properties of LDL-TG. We investigated similarities or differences between LDL-TG and sdLDL-C.

    Methods: Fasting plasma was obtained from 1,085 patients with type 2 diabetes who were enrolled in the diabetes regional cohort study (ViNA Cohort). LDL-TG and sdLDL-C concentrations were measured using a homogeneous assay established by us. In a subset of subjects, LDL-TG and sdLDL-C levels were measured postprandially or after treatment with lipid-lowering drugs.

    Results: In a quartile analysis, higher LDL-TG quartiles were associated with higher frequency of female and fibrate users, whereas sdLDL-C quartiles were associated with frequency of men, drinking, and metabolic syndrome-related measurements. Higher quartiles of LDL-TG/LDL-C were associated with smoking, drinking, fibrate users, and statin users. LDL-TG was significantly correlated with TG, LDL-C, sdLDL-C, and apolipoprotein (apo) B, with apoB being the primary determinant. LDL-TG correlated to high sensitive C-reactive protein (CRP) independently of other lipids. Mean LDL-TG did not change with fasting/non-fasting. Statin treatment reduced LDL-TG, whereas fibrates increased it, but these drugs reduced sdLDL-C equally.

    Conclusions: LDL-TG levels were more tightly regulated by the number of LDL particles than plasma TG levels were. SdLDL-C was closely associated with metabolic syndrome-related factors, whereas LDL-TG was associated with low-grade systemic inflammation.

  • Tomohiro Komatsu, Makoto Ayaori, Harumi Uto-Kondo, Katsumi Hayashi, Ka ...
    Subject area: Original Article
    2022 Volume 29 Issue 5 Pages 775-784
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
    Advance online publication: May 01, 2021
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    Aims: Inflammation is involved in various processes of atherosclerosis development. Serum C-reactive protein (CRP) levels, a predictor for cardiovascular risk, are reportedly reduced by statins. However, several studies have demonstrated that CRP is a bystander during atherogenesis. While S100A12 has been focused on as an inflammatory molecule, it remains unclear whether statins affect circulating S100A12 levels. Here, we investigated whether atorvastatin treatment affected S100A12 and which biomarkers were correlated with changes in arterial inflammation.

    Methods: We performed a prospective, randomized open-labeled trial on whether atorvastatin affected arterial (carotid and thoracic aorta) inflammation using 18fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) and inflammatory markers. Thirty-one statin-naïve patients with carotid atherosclerotic plaques were randomized to either a group receiving dietary management (n=15) or one receiving atorvastatin (10mg/day, n=16) for 12weeks. 18F-FDG-PET/CT and flow-mediated vasodilation (FMD) were performed, the latter to evaluate endothelial function.

    Results: Atorvastatin, but not the diet-only treatment, significantly reduced LDL-cholesterol (LDL-C, -43%), serum CRP (-37%) and S100A12 levels (-28%) and improved FMD (+38%). 18F-FDG-PET/CT demonstrated that atorvastatin, but not the diet-only treatment, significantly reduced accumulation of 18F-FDG in the carotid artery and thoracic aorta. A multivariate analysis revealed that reduction in CRP, S100A12, LDL-C, oxidized-LDL, and increase in FMD were significantly associated with reduced arterial inflammation in the thoracic aorta, but not in the carotid artery.

    Conclusions: Atorvastatin treatment reduced S100A12/CRP levels, and the changes in these circulating markers mirrored the improvement in arterial inflammation. Our observations suggest that S100A12 may be an emerging therapeutic target for atherosclerosis.

  • Kentaro Ishizuka, Sono Toi, Takao Hoshino, Eiko Higuchi, Kazuo Kitagaw ...
    Subject area: Original Article
    2022 Volume 29 Issue 5 Pages 785-793
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
    Advance online publication: May 01, 2021
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    Aim: Embolic stroke of undetermined source (ESUS) is a clinical construct introduced to describe cryptogenic stroke cases with ambiguous diagnoses. Cardiac causes are recognized as a major cause of ESUS, Patent foramen ovale (PFO) being among them. We aimed to investigate the relationship between infarct patterns and PFO in patients with ESUS.

    Methods: We evaluated 190 consecutive patients with ESUS registered in the Tokyo Women’s Medical University Stroke Registry. Among them, 94 patients who underwent magnetic resonance imaging and angiography, as well as transthoracic and transesophageal echocardiography, were included in this study. The infarct patterns were classified according to location (infratentorial or non-infratentorial lesions), size (small or large infarcts), and number (single or multiple lesions).

    Results: Prevalence of PFO was significantly higher in patients in the infratentorial than those in the non-infratentorial lesion group (40.7% versus 14.9%, respectively; P=0.007). However, neither lesion size nor number were associated with PFO. In multivariate logistic regression analysis, the presence of infratentorial lesions was independently associated with PFO in ESUS patients (odds ratio: 2.18; 95% confidence interval: 1.24-3.95; P<0.007). In 21 patients with PFO, large PFOs were more prevalent in the infratentorial than in the non-infratentorial lesion group.

    Conclusions: Infratentorial lesions may be independently associated with PFO in patients with ESUS. The presence of infratentorial lesions could predict the presence of PFO in ESUS cases.

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