Journal of Atherosclerosis and Thrombosis
Online ISSN : 1880-3873
Print ISSN : 1340-3478
ISSN-L : 1340-3478
Advance online publication
Showing 1-50 articles out of 131 articles from Advance online publication
  • Atsuko Nakayama, Hiroyuki Morita, Tatsuyuki Sato, Takuya Kawahara, Nor ...
    Type: Original Article
    Article ID: 62889
    Published: 2021
    [Advance publication] Released: May 14, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    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.

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  • Masahiro Koseki, Shizuya Yamashita, Masatsune Ogura, Yasushi Ishigaki, ...
    Type: Review
    Article ID: RV17053
    Published: 2021
    [Advance publication] Released: May 14, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Tangier disease is a genetic disorder characterized by an absence or extremely low level of high-density lipoprotein (HDL)-cholesterol (HDL-C). It is caused by a dysfunctional mutation of the ATP-binding cassette transporter A1 (ABCA1) gene, the mandatory gene for generation of HDL particles from cellular cholesterol and phospholipids, and it appears in an autosomal recessive hereditary profile. To date, 35 cases have been reported in Japan and 109 cases outside Japan. With dysfunctional mutations in both alleles (homozygotes or compound heterozygotes), the HDL-C level is mostly less than 5 mg/dL and there is 10 mg/dL or less of apolipoprotein A-I (apoA-I), the major protein component of HDL. In patients with Tangier disease, major physical findings are orange-colored pharyngeal tonsils, hepatosplenomegaly, corneal opacity, lymphadenopathy, and peripheral neuropathy. Although patients tend to have decreased low-density lipoprotein (LDL)-cholesterol (LDL-C) levels, premature coronary artery disease is frequently observed. No specific curative treatment is currently available, so early identification of patients and preventing atherosclerosis development are crucial. Management of risk factors other than low HDL-C is also important, such as LDL-C levels, hypertension and smoking. Additionally, treatment for glucose intolerance might be required because impaired insulin secretion from pancreatic beta cells has occasionally been reported.

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  • Shizuya Yamashita, Daisaku Masuda, Mariko Harada-Shiba, Hidenori Arai, ...
    Type: Original Article
    Article ID: 62764
    Published: 2021
    [Advance publication] Released: May 13, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    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.

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  • Hiroaki Okazaki, Takanari Gotoda, Masatsune Ogura, Shun Ishibashi, Kyo ...
    Type: Review
    Article ID: RV17054
    Published: 2021
    [Advance publication] Released: May 13, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Primary chylomicronemia (PCM) is a rare and intractable disease characterized by marked accumulation of chylomicrons in plasma. The levels of plasma triglycerides (TGs) typically range from 1,000 - 15,000 mg/dL or higher.

    PCM is caused by defects in the lipoprotein lipase (LPL) pathway due to genetic mutations, autoantibodies, or unidentified causes. The monogenic type is typically inherited as an autosomal recessive trait with loss-of-function mutations in LPL pathway genes (LPL, LMF1, GPIHBP1, APOC2, and APOA5). Secondary/environmental factors (diabetes, alcohol intake, pregnancy, etc.) often exacerbate hypertriglyceridemia (HTG).

    The signs, symptoms, and complications of chylomicronemia include eruptive xanthomas, lipemia retinalis, hepatosplenomegaly, and acute pancreatitis with onset as early as in infancy. Acute pancreatitis can be fatal and recurrent episodes of abdominal pain may lead to dietary fat intolerance and failure to thrive.

    The main goal of treatment is to prevent acute pancreatitis by reducing plasma TG levels to at least less than 500-1,000 mg/dL. However, current TG-lowering medications are generally ineffective for PCM. The only other treatment options are modulation of secondary/environmental factors. Most patients need strict dietary fat restriction, which is often difficult to maintain and likely affects their quality of life.

    Timely diagnosis is critical for the best prognosis with currently available management, but PCM is often misdiagnosed and undertreated. The aim of this review is firstly to summarize the pathogenesis, signs, symptoms, diagnosis, and management of PCM, and secondly to propose simple diagnostic criteria that can be readily translated into general clinical practice to improve the diagnostic rate of PCM. In fact, these criteria are currently used to define eligibility to receive social support from the Japanese government for PCM as a rare and intractable disease.

    Nevertheless, further research to unravel the molecular pathogenesis and develop effective therapeutic modalities is warranted. Nationwide registry research on PCM is currently ongoing in Japan with the aim of better understanding the disease burden as well as the unmet needs of this life-threatening disease with poor therapeutic options.

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  • Shingo Koyama, Yoshiki Sekijima, Masatsune Ogura, Mika Hori, Kota Mats ...
    Type: Review
    Article ID: RV17055
    Published: 2021
    [Advance publication] Released: May 08, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disorder caused by mutations in the CYP27A1 gene, which encodes the mitochondrial enzyme sterol 27-hydroxylase. Decreased sterol 27-hydroxylase activity results in impaired bile acid synthesis, leading to reduced production of bile acids, especially chenodeoxycholic acid (CDCA), as well as elevated serum cholestanol and urine bile alcohols. The accumulation of cholestanol and cholesterol mainly in the brain, lenses, and tendons results in the characteristic clinical manifestations of CTX. Clinical presentation is characterized by systemic symptoms including neonatal jaundice or cholestasis, refractory diarrhea, juvenile cataracts, tendon xanthomas, osteoporosis, coronary heart disease, and a broad range of neuropsychiatric manifestations. The combinations of symptoms vary from patient to patient and the presenting symptoms, especially in the early disease phase, may be nonspecific, which leads to a substantial diagnostic delay or underdiagnosis. Replacement of CDCA has been approved as a first-line treatment for CTX, and can lead to biochemical and clinical improvements. However, the effect of CDCA treatment is limited once significant neuropsychiatric manifestations are established. The age at diagnosis and initiation of CDCA treatment correlate with the prognosis of patients with CTX. Therefore, early diagnosis and subsequent treatment initiation are essential.

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  • Kentaro Ishizuka, Sono Toi, Takao Hoshino, Eiko Higuchi, Kazuo Kitagaw ...
    Type: Original Article
    Article ID: 61200
    Published: 2021
    [Advance publication] Released: May 01, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    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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  • Tomohiro Komatsu, Makoto Ayaori, Harumi Uto-Kondo, Katsumi Hayashi, Ka ...
    Type: Original Article
    Article ID: 61630
    Published: 2021
    [Advance publication] Released: May 01, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    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.

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  • Tsutomu Hirano, Rieko Kodera, Takeshi Hirashima, Natsuko Suzuki, Ema A ...
    Type: Original Article
    Article ID: 62789
    Published: 2021
    [Advance publication] Released: April 29, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    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.

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  • Takuya Matsumoto, Shinichiro Yoshino, Tadashi Furuyama, Koichi Morisak ...
    Type: Original Article
    Article ID: 58941
    Published: 2021
    [Advance publication] Released: April 28, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    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.

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  • Hayato Tada, Akihiro Nomura, Masatsune Ogura, Katsunori Ikewaki, Yasus ...
    Type: Review
    Article ID: RV17052
    Published: 2021
    [Advance publication] Released: April 28, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Sitosterolemia is an inherited metabolic disorder characterized by increased levels of plant sterols, such as sitosterol. This disease is caused by loss-of-function genetic mutations in ATP-binding cassette (ABC) subfamily G member 5 or member 8 (ABCG5 or ABCG8, respectively), both of which play important roles in selective excretion of plant sterols from the liver and intestine, leading to failure to prevent absorption of food plant sterols. This disorder has been considered to be extremely rare. However, accumulated clinical data as well as genetics suggest the possibility of a much higher prevalence. Its clinical manifestations resemble those observed in patients with familial hypercholesterolemia (FH), including tendon xanthomas, hyper LDL-cholesterolemia, and premature coronary atherosclerosis. We provide an overview of this recessive genetic disease, diagnostic as well as therapeutic tips, and the latest diagnostic criteria in Japan.

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  • Yoshinori Tsubakimoto
    Type: Editorial
    Article ID: ED168
    Published: 2021
    [Advance publication] Released: April 21, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION
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  • Hidenori Arai, Hideaki Bujo, Daisaku Masuda, Toshiyuki Ishibashi, Sato ...
    Type: Original Article
    Article ID: 62821
    Published: 2021
    [Advance publication] Released: April 18, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Aims: In this study, we integrated two randomized control trials, PROSPECTIVE and IMPACT, to address the effect of probucol on cerebrocardiovascular events and carotid intima-media thickness (IMT) in Japanese, Korean, and Chinese patients with coronary artery disease (CAD).

    Methods: A total of 1,025 patients from the PROSPECTIVE and IMPACT studies were enrolled. The time to the first major adverse cerebrocardiovascular event, in addition to carotid IMT and lipid levels, was compared between the control and probucol groups.

    Results: In the integrated analysis, the adjusted hazard ratio (HR) and 95% confidence interval (CI) were 0.67 and 0.44–1.03, respectively, indicating a tendency to show the effect of probucol on cerebrocardiovascular events in secondary prevention. We also found no significant differences between the control and probucol groups in the mean IMT of the carotid arteries and its changes. However, we found a significant decrease in cerebrocardiovascular events in patients with reduced levels of HDL cholesterol (HDL-C) (≥ 6.25 mg/dL) compared with those with levels <6.25 mg/dL (p=0.024), without any increase in adverse events such as severe ventricular arrhythmias.

    Conclusion: We demonstrated a marginal effect of probucol on cerebrocardiovascular events in Asian patients with CAD, with reasonable safety profiles. A larger study may be needed to support the effect of probucol for cardiovascular prevention.

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  • Atsushi Nohara, Hayato Tada, Masatsune Ogura, Sachiko Okazaki, Koh Ono ...
    Type: Review
    Article ID: RV17050
    Published: 2021
    [Advance publication] Released: April 18, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Familial hypercholesterolemia (FH) is an inherited disorder with retarded clearance of plasma LDL caused by mutations of the genes involved in the LDL receptor-mediated pathway and most of them exhibit autosomal dominant inheritance. Homozygotes of FH (HoFH) may have plasma LDL-C levels, which are at least twice as high as those of heterozygous FH (HeFH) and therefore four times higher than normal levels. Prevalence of HoFH had been estimated as 1 in 1,000,000 before but more recent genetic analysis surveys predict 1 in 170,000 to 300,000. Since LDL receptor activity is severely impaired, HoFH patients do not or very poorly respond to medications to enhance activity, such as statins, and have a poorer prognosis compared to HeFH. HoFH should therefore be clinically distinguished from HeFH. Thorough family studies and genetic analysis are recommended for their accurate diagnosis. Fatal cardiovascular complications could develop even in the first decade of life for HoFH, so aggressive lipid-lowering therapy should be initiated as early as possible. Direct removal of plasma LDL by lipoprotein apheresis has been the principal measure for these patients. However, this treatment alone may not achieve stable LDL-C target levels and combination with drugs should be considered. The lipid-lowering effects of statins and PCSK9 inhibitors substantially vary depending on the remaining LDL receptor activity of individual patients. On the other hand, the action an MTP inhibitor is independent of LDL receptor activity, and it is effective in most HoFH cases. This review summarizes the key clinical issues of HoFH as well as insurance coverage available under the Japanese public healthcare system.

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  • Masayuki Kuroda, Hideaki Bujo, Koutaro Yokote, Takeyoshi Murano, Takas ...
    Type: Review
    Article ID: RV17051
    Published: 2021
    [Advance publication] Released: April 18, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Lecithin cholesterol acyltransferase (LCAT) is a lipid-modification enzyme that catalyzes the transfer of the acyl chain from the second position of lecithin to the hydroxyl group of cholesterol (FC) on plasma lipoproteins to form cholesteryl acylester and lysolecithin. Familial LCAT deficiency is an intractable autosomal recessive disorder caused by inherited dysfunction of the LCAT enzyme. The disease appears in two different phenotypes depending on the position of the gene mutation: familial LCAT deficiency (FLD, OMIM 245900) that lacks esterification activity on both HDL and ApoB-containing lipoproteins, and fish-eye disease (FED, OMIM 136120) that lacks activity only on HDL. Impaired metabolism of cholesterol and phospholipids due to LCAT dysfunction results in abnormal concentrations, composition and morphology of plasma lipoproteins and further causes ectopic lipid accumulation and/or abnormal lipid composition in certain tissues/cells, and serious dysfunction and complications in certain organs. Marked reduction of plasma HDL-cholesterol (HDL-C) and corneal opacity are common clinical manifestations of FLD and FED. FLD is also accompanied by anemia, proteinuria and progressive renal failure that eventually requires hemodialysis. Replacement therapy with the LCAT enzyme should prevent progression of serious complications, particularly renal dysfunction and corneal opacity. A clinical research project aiming at gene/cell therapy is currently underway.

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  • Senta Gewalt, Shqipdona Lahu, Gjin Ndrepepa, Costanza Pellegrini, Isab ...
    Type: Original Article
    Article ID: 62776
    Published: 2021
    [Advance publication] Released: April 16, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    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.

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  • Eri Toda Kato, Shinya Goto
    Type: Review
    Article ID: RV17049
    Published: 2021
    [Advance publication] Released: April 13, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality across the world, warranting continuous research in this field. The elucidation of the atherogenesis mechanism is considered one of the most relevant scientific accomplishments of the last century. This has led to the clinical development of various novel therapeutic interventions for patients with or at risk of ASCVD, in which randomized clinical trials played a crucial role.

    The Thrombolysis in Myocardial Infarction (TIMI) Study Group was initially established to conduct a clinical trial studying thrombolysis for treatment of myocardial infarction. However, over the years, the TIMI Study Group has expanded their research interests to include antithrombotic therapy, lipid lowering, anti-diabetes, anti-obesity, and even heart failure. By leading large-scale, international, randomized, controlled trials of novel therapeutics, the TIMI Study Group has helped shape the very practice of cardiovascular medicine for over a quarter of a century, and decades of research continue to provide future promise for further advancement. Through a mutual goal to improve the care of ASCVD patients, the Japanese scientific community has become one of the important contributors to the TIMI Study Group's clinical research.

    In this review article, the authors aim to summarize major research lead by the TIMI Study Group in the ASCVD field.

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  • Yuting Tan, Fang Nie, Guode Wu, Fangzhou Guo, Yanqing Wang, Longli Wan ...
    Type: Original Article
    Article ID: 61275
    Published: 2021
    [Advance publication] Released: April 08, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Aim: H-type hypertension is connected with carotid atherosclerotic plaques and stroke, whereas neovascularization is a dominant contributor to plaque vulnerability. However, the correlation between H-type hypertension and plaque vulnerability remains unclear. This study aims to explore the influence of H-type hypertension on intraplaque neovascularization (IPN).

    Methods: We enrolled 235 patients with carotid plaques into the investigation and classified them into four groups: H-type hypertension group, simple hypertension group, isolated hyperhomocysteinemia group, and control group. Contrast-enhanced ultrasound (CEUS) was performed on them and IPN was evaluated using semi-quantitative visual grading: grade 1 (no microbubbles or microbubbles limited to the adventitial side and/or shoulder of plaque) and, grade 2 (diffused microbubbles within plaque or microbubbles enter plaque core). To analyze the correlation between H-type hypertension and the degree of plaque enhancement, logistic regression was used.

    Results: Compared with those with CEUS grade 1 plaques, those with CEUS grade 2 plaques had higher frequency of ischemic stroke (29.0% vs. 45.1%, P<0.05), hypertension (41.0% vs. 56.3%, P<0.05), and H-type hypertension (18.0% vs. 29.6%, P<0.05). No significant differences existed in plaque morphology, plaque echogenicity, and the severity of carotid artery stenosis between the degree of plaque enhancement (all P >0.05). H-type hypertension (multivariate-adjusted OR: 3.036, 95% CI: 1.258–7.329) was independently connected with the degree of plaque enhancement even after adjusting for other covariates.

    Conclusion: H-type hypertension is expressly connected with the degree of plaque enhancement and may facilitate plaque vulnerability. Our findings may offer a new insight for treating vulnerable plaque, lowering blood pressure, and lowering homocysteine equally crucial.

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  • Koutatsu Maruyama, Saori Miyazaki, Satomi Minato-Inokawa
    Type: Editorial
    Article ID: ED166
    Published: 2021
    [Advance publication] Released: April 07, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION
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  • Michihiro Satoh
    Type: Editorial
    Article ID: ED167
    Published: 2021
    [Advance publication] Released: April 07, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION
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  • Keisuke Kojima, Daisuke Fukamachi, Yasuo Okumura
    Type: Correspondence
    Article ID: 62890
    Published: 2021
    [Advance publication] Released: April 03, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION
    Supplementary material

    We have a great interest in the article in Journal of Atherosclerosis and Thrombosis by Suzuki et al. titled Complex Aortic Arch Atherosclerosis in Acute Ischemic Stroke Patients with Non-Valvular Atrial Fibrillation. The authors demonstrated that 38.7% transesophageal echocardiography-derived complex aortic arch plaques (CAPs) among 106 patients with acute ischemic strokes with atrial fibrillation (AF), suggesting that patients with acute ischemic stroke and AF often had CAPs. The atheromatous lesions at the aortic arch are one of the causes of ischemic strokes. The cause of acute ischemic strokes in patients with AF could not only be cardiogenic embolisms due to AF but also aortogenic embolisms due to CAPs. The possibility of concomitant CAPs should be considered for stroke patients with AF. Non-obstructive general angioscopy has the possibility to detect aortic plaques in the aortic arch more accurately than TEE and might help to diagnose atheromatous plaques and embolic materials in the aortic arch. Further studies are needed to elucidate the causes of ischemic strokes and are expected to improve the outcomes for acute ischemic strokes in patients with AF.

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  • Tetsuji Morishita, Daisuke Takada, Jung-ho Shin, Takuya Higuchi, Susum ...
    Type: Original Article
    Article ID: 62746
    Published: 2021
    [Advance publication] Released: April 01, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    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.

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  • Junji Kobayashi
    Type: Editorial
    Article ID: ED170
    Published: 2021
    [Advance publication] Released: April 01, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION
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  • Hiroyuki Naito, Tomohisa Nezu, Naohisa Hosomi, Daisuke Kuzume, Shiro A ...
    Type: Original Article
    Article ID: 62795
    Published: 2021
    [Advance publication] Released: March 30, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    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.

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  • Kumiko Suto, Daiju Fukuda, Masakazu Shinohara, Byambasuren Ganbaatar, ...
    Type: Original Article
    Article ID: 61101
    Published: 2021
    [Advance publication] Released: March 27, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Aims: Various pathological processes related to diabetes cause endothelial dysfunction. Eicosanoids derived from arachidonic acid (AA) have roles in vascular regulation. Fibrates have recently been shown to attenuate vascular complications in diabetics. Here we examined the effects of pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, on plasma eicosanoid levels and endothelial function in diabetic mice.

    Methods: Diabetes was induced in 7-week-old male wild-type mice by a single injection of streptozotocin (150 mg/kg). Pemafibrate (0.3 mg/kg/day) was administered orally for 3 weeks. Untreated mice received vehicle. Circulating levels of eicosanoids and free fatty acids were measured using both gas and liquid chromatography-mass spectrometry. Endothelium-dependent and endothelium-independent vascular responses to acetylcholine and sodium nitroprusside, respectively, were analyzed.

    Results: Pemafibrate reduced both triglyceride and non-high-density lipoprotein -cholesterol levels (P<0.01), without affecting body weight. It also decreased circulating levels of AA (P<0.001), thromboxane B2 (P<0.001), prostaglandin E2, leukotriene B4 (P<0.05), and 5-hydroxyeicosatetraenoic acid (P<0.001), all of which were elevated by the induction of diabetes. In contrast, the plasma levels of 15-deoxy-Δ12,14-prostaglandin J2, which declined following diabetes induction, remained unaffected by pemafibrate treatment. In diabetic mice, pemafibrate decreased palmitic acid (PA) and stearic acid concentrations (P<0.05). Diabetes induction impaired endothelial function, whereas pemafibrate ameliorated it (P<0.001). The results of ex vivo experiments indicated that eicosanoids or PA impaired endothelial function.

    Conclusion: Pemafibrate diminished the levels of vasoconstrictive eicosanoids and free fatty acids accompanied by a reduction of triglyceride. These effects may be associated with the improvement of endothelial function by pemafibrate in diabetic mice.

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  • Daisuke Fujioka, Yosuke Watanabe, Takamitsu Nakamura, Takashi Yokoyama ...
    Type: Original Article
    Article ID: 62216
    Published: 2021
    [Advance publication] Released: March 27, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    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.

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  • Daisaku Masuda, Shizuya Yamashita
    Type: Editorial
    Article ID: ED165
    Published: 2021
    [Advance publication] Released: March 24, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION
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  • Jiaqi Li, Hironori Imano, Kazumasa Yamagishi, Mari Tanaka, Renzhe Cui, ...
    Type: Original Article
    Article ID: 60889
    Published: 2021
    [Advance publication] Released: March 21, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Aim: This study aimed to investigate the associations of leukocyte count with the risks of stroke and coronary heart disease among the general Japanese population.

    Methods: A total of 5,242 residents aged 40–69 years living in two Japanese communities underwent leukocyte count measurements between 1991 and 2000, and the data were updated using 5- or 10-year follow-ups or both. Participants who had histories of stroke, coronary heart disease, or high values of leukocyte count (>130×102 cells/mm3) were excluded. Hazard ratios with 95% confidence intervals (CIs) were calculated according to quartiles of cumulative average leukocyte count.

    Results: During follow-up of 21 years, 327 stroke and 130 coronary heart disease cases were determined. After adjustments for age, sex, community, and updated cardiovascular risk factors, the multivariable hazard ratio (95% CI) for the highest versus lowest quartile of leukocyte count was 1.50 (1.08–2.08) for ischemic stroke, 1.59 (1.00–2.51) for lacunar infarction, 1.42 (0.90–2.26) for non-lacunar infarction, 2.17 (1.33–3.55) for coronary heart disease, and 1.40 (1.11–1.76) for total cardiovascular disease. In smoking status-stratified analyses, the corresponding multivariable hazard ratio (95% CI) was 2.45 (1.11–5.38) for ischemic stroke, 2.73 (1.37–5.44) for coronary heart disease in current smokers, 2.42 (1.07–5.46), 1.55 (0.58–4.15) in former smokers, and 1.17 (0.75–1.82), 1.78 (0.83–3.82) in never smokers.

    Conclusion: Leukocyte count was positively associated with the risks of ischemic stroke and coronary heart disease among the general Japanese population, especially in current smokers.

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  • Naotaka Akutsu, Koichiro Hori, Saki Mizobuchi, Akihito Ogaku, Yutaka K ...
    Type: Original Article
    Article ID: 60954
    Published: 2021
    [Advance publication] Released: March 21, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Aims: Smaller low-density lipoprotein (LDL) particle size has been suggested to result in the development of endothelial dysfunction, atherosclerosis, and in-stent restenosis (ISR); however, little is known regarding the impact of the LDL particle size on the neointima formation leading to ISR after everolimus-eluting stent (EES) implantation.

    Methods: In this study, we have included 100 patients to examine the relationship between an LDL-C/apolipoprotein B (Apo B) ≤ 1.2, reportedly representing the LDL particle size, and the neointimal characteristics using optical coherence tomography (OCT) and coronary angioscopy (CAS) during the follow-up coronary angiography (CAG) period (8.8±2.5 months) after EES implantation. We divided them into two groups: LDL-C/Apo B ≤ 1.2 group (low LDL-C/Apo B group, n=53) and LDL-C/Apo B >1.2 group (high LDL-C/Apo B group, n=47).

    Results: The low LDL-C/Apo B group had a significantly larger neointimal volume (12.8±5.3 vs. 10.3±4.9 mm3, p=0.021) and lower incidence of a neointimal homogeneous pattern (71 vs. 89 %), higher incidence of a neointimal heterogeneous pattern (25 vs. 9 %) (p=0.006) and higher prevalence of macrophage accumulation (9 vs. 2 %) (p=0.030) as assessed via OCT, and, as per the CAS findings, a higher prevalence of yellow grade ≥ 2 (grade 2; adjusted residual: 2.94, grade 3; adjusted residual: 2.00, p=0.017) than the high LDL-C/Apo B group.

    Conclusions: A low LDL-C/Apo B ratio was found to be strongly associated with neointimal proliferation and neointimal instability evidenced chronically by OCT and CAS. An LDL-C/Apo B ≤ 1.2 will be of aid in terms of identifying high-risk patients after EES implantation.

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  • Jonathan Golledge, Aaron Drovandi
    Type: Review
    Article ID: 62778
    Published: 2021
    [Advance publication] Released: March 21, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Patients with lower limb artery stenosis or occlusion (peripheral artery disease; PAD) have been determined to be at very high risk of both major adverse cardiovascular events, such as myocardial infarction and stroke, and major adverse limb events, such as amputation and requirement for artery surgery.

    Effective medical management has been identified as key in reducing this risk; however, this is often poorly implemented in clinical practice. Thus, the aim of this narrative review was to summarize the current evidence on the medical management of PAD in order to inform clinicians and highlight recommendations for clinical practice. International guidelines, randomized controlled trials, and relevant systematic reviews and meta-analyses have been included in this study. The focus was the management of the key modifiable risk factors to mitigate possible adverse events through prescription of anti-platelet and anticoagulation drugs and medications to control low-density lipoprotein cholesterol, blood pressure, and diabetes and aid smoking cessation. The available evidence from randomized clinical trials provide a strong rationale for the need for holistic medical management programs that are effective in achieving uptake of these medical therapies in patients with PAD. In conclusion, people with PAD have some of the highest adverse event rates among those with cardiovascular diseases. Secondary preventive measures have been proven effective in reducing these adverse events; however, they remain to be adequately implemented. Thus, the need for an effective implementation program has emerged to reduce adverse events in this patient group.

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  • Hao-Yu Wang, Dong Yin, Yan-Yan Zhao, Rui Zhang, Yue-Jin Yang, Bo Xu, K ...
    Type: Original Article
    Article ID: 60129
    Published: 2021
    [Advance publication] Released: March 20, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Aims: The ESC/EACTS myocardial revascularization guidelines recently standardized the definition of patients at high ischemic risk (HIR). However, the ability of ESC/EACTS-HIR criteria to stratify ischemic and bleeding risk in a contemporary real-world East Asian cohort remains unexplored.

    Methods: A total of 10,167 consecutive patients undergoing PCI from prospective Fuwai PCI Registry (January 2013 to December 2013) were reviewed. ESC/EACTS-HIR features was defined as having at least one of the eight clinical and angiographic characteristics. The primary ischemic endpoint was target vessel failure (cardiac death, target vessel myocardial infarction [MI], or target vessel revascularization [TVR]); bleeding outcome was assessed using the BARC type 2, 3, or 5 bleeding. Median follow-up was 29 months.

    Results: Compared with non-HIR patients, HIR patients (n=5,149, 50.6%) were associated with increased risk for target vessel failure (adjusted hazard ratio [HRadjust]: 1.48 [1.25-1.74]) and patient-oriented composite outcome (HRadjust: 1.44 [1.28-1.63]), as well as cardiac death, MI, and TVR. By contrast, the risk of clinically relevant bleeding was not significantly different between the two groups. (HRadjust: 0.84 [0.66-1.06]). Greater than or equal to three implanted stents and diabetic patients with diffuse multivessel coronary disease emerged as independent predictors for long-term adverse outcomes. There was no significant interaction between high bleeding risk (HBR) status and clinical outcomes associated with ESC/EACTS-HIR criteria (all Pinteraction >0.05).

    Conclusion: The ESC/EACTS-HIR features identified patients at increased risk of thrombotic events, including cardiac death, but not for clinically relevant bleeding. Importantly, HBR did not modify cardiovascular risk subsequent to patients with ESC/EACTS-HIR features, suggesting its potential clinical applicability in tailoring antithrombotic therapy.

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  • Yuko Horikoshi, Shin-ichiro Katsuda, Yuko Fujikura, Akihiro Hazama, Hi ...
    Type: Original Article
    Article ID: 60848
    Published: 2021
    [Advance publication] Released: March 20, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Aim: The cardio-ankle vascular index (CAVI) consists of intrinsic and functional arterial stiffness mainly regulated by vasoactive compounds. A new stiffness index of the aorta (aBeta) and iliac-femoral arteries (ifBeta) was determined by applying the CAVI theory to the whole aorta and iliac-femoral arteries. We investigated the changes in aBeta and ifBeta in response to decreased blood pressure (BP) induced by the Ca2+ channel blocker nicardipine to elucidate the involvement of Ca2+ in aBeta and ifBeta.

    Methods: Pressure waves at the origin of the aorta (oA), distal end of the abdominal aorta (dA), and left femoral artery (fA) as well as flow waves at the oA were simultaneously recorded before and after the infusion of nicardipine (50 µg/kg/min) for 2 min in 12 male rabbits under pentobarbital anesthesia. Beta was calculated using the following formula: Beta=2ρ / PP×ln (SBP / DBP)×PWV2, where ρ, SBP, DBP, and PP denote blood density and systolic, diastolic, and pulse pressures, respectively. aBeta, ifBeta, and aortic-iliac-femoral Beta (aifBeta) were calculated using aPWV, ifPWV, and aifPWV, respectively.

    Results: SBP, mean arterial pressure (MAP), DBP, and total peripheral vascular resistance significantly decreased during the administration of nicardipine, whereas cardiac output significantly increased. aBeta and ifBeta significantly increased and decreased, respectively, whereas aifBeta did not change despite the decrease in BP. ifBeta and aBeta positively and negatively correlated with BP, respectively, whereas aifBeta did not correlate with SBP.

    Conclusions: There were contradictory arterial responses to nicardipine between the elastic and muscular arteries. Unknown vasoconstriction mechanisms that are not involved in Ca2+ influx may function in the aorta in response to decreased BP.

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  • Pingting Zhong, Jie Qin, Zhixi Li, Lei Jiang, Qingsheng Peng, Manqing ...
    Type: Original Article
    Article ID: 62059
    Published: 2021
    [Advance publication] Released: March 19, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    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.

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  • Takumi Matsumura, Tomoko Sankai, Kazumasa Yamagishi, Yasuhiko Kubota, ...
    Type: Original Article
    Article ID: 60103
    Published: 2021
    [Advance publication] Released: March 16, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Aim: We aimed to examine the impact of high-risk levels of cardiovascular risk factors on the incidence of cardiovascular disease (CVD) in overweight and non-overweight individuals without treatment for the risk factors.

    Methods: A total of 8,051 individuals aged 40–74 years without a history of CVD and/or without treatment for hypertension, diabetes, hyperlipidemia, and kidney disease at baseline in 1995–2000 were followed up for a median of 14.1 years. We classified the participants into three risk categories (low-, intermediate-, and high-risk groups) on the basis of individual risk factors (blood pressure, serum glucose, low-density lipoprotein cholesterol [LDL-C], and urinary protein) according to the guidelines of Japanese clinical societies. The high-risk group (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg, fasting serum glucose ≥ 130 mg/dL or non-fasting serum glucose ≥ 180 mg/dL, LDL-C ≥ 180 mg/dL, proteinuria ≥ 2+) needed to refer to physicians or start treatment immediately. Overweight was defined as a body mass index of ≥ 25 kg/m2.

    Results: Compared with those in the non-overweight low-risk group, the hazard ratios (HRs) (95% confidence intervals, population-attributable fractions [PAFs]) of CVD in the high-risk categories of blood pressure were 2.0 (1.4–2.9, 7.0%) in the non-overweight high-risk group and 2.9 (1.9–4.3, 6.8%) in the overweight high-risk group. The corresponding HRs (95% confidence intervals, PAFs) of serum glucose were 2.0 (1.2–3.4, 2.5%) and 2.2 (1.1–4.3, 1.5%) in the non-overweight and overweight high-risk groups, respectively. Such associations were not observed for the high-risk group of LDL-C and proteinuria.

    Conclusions: The present long-term observational study implies that targeting persons with non-treated severe hypertension and diabetes is prioritized to prevent CVD regardless of overweight status.

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  • Mizuki Sata, Tomonori Okamura, Sei Harada, Daisuke Sugiyama, Kazuyo Ku ...
    Type: Original Article
    Article ID: 58719
    Published: 2021
    [Advance publication] Released: March 06, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Aims: The categories in the comprehensive lipid and risk management guidelines were proposed by the Japan Atherosclerosis Society (JAS Guidelines 2017), which adopted the estimated 10 year absolute risk of coronary artery disease (CAD) incidence in the Suita score. We examined whether those categories were concordant with the degree of arterial stiffness.

    Methods: In 2014, the cardio-ankle vascular index (CAVI), an arterial stiffness parameter, was measured in 1,972 Japanese participants aged 35–74 years in Tsuruoka City, Yamagata Prefecture, Japan. We examined the mean CAVI and the proportion and odds ratios (ORs) of CAVI ≥ 9.0 on the basis of the following three management classifications using the analysis of variance and logistic regression: “Category I (Low risk),” “Category II (Middle risk),” and “Category III (High risk).”

    Results: The mean CAVI and proportion of CAVI ≥ 9.0 were 8.6 and 34.8% among males and 8.1 and 18.3% among females, respectively. The mean CAVI and proportion of CAVI ≥ 9.0 were associated with an estimated 10 year absolute risk for CAD among males and females, excluding High risk for females. These results were similar to the management classification by the guideline: the multivariable-adjusted ORs (95% confidence intervals) of CAVI ≥ 9.0 among Category II and Category III compared with those among Category I were 2.96 (1.61–5.43) and 7.33 (4.03–13.3) for males and 3.99 (2.55–6.24) and 3.34 (2.16–5.16) for females, respectively.

    Conclusions: The risk stratification, which was proposed in the JAS Guidelines 2017, is concordant with the arterial stiffness parameter.

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  • Korehito Iida, Takafumi Hiro, Daisuke Fukamachi, Mitsumasa Sudo, Toshi ...
    Type: Original Article
    Article ID: 60509
    Published: 2021
    [Advance publication] Released: March 02, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Aim: Coronary plaque rupture is the main cause of acute coronary syndrome (ACS), but the role of blood flow features around plaque rupture for ACS is still unknown. The present study aimed to assess the relationship between the geometric configuration of ruptured plaque and ACS occurrence using computational fluid dynamics (CFD) by moving particle method in patients with coronary artery disease.

    Methods: In this study, 45 patients with coronary artery disease who underwent three-dimensional intravascular ultrasound (IVUS) and had a coronary ruptured plaque (24 plaques with provoked ACS, 21 without) were included. To compare the difference in blood flow profile around ruptured plaque between the patients with and without ACS, the IVUS images were analyzed via the novel CFD analysis.

    Results: There were no significant differences in localized flow profile around ruptured plaque between the two groups when the initial particle velocity was 10.0 cm/s corresponded to a higher coronary flow velocity at ventricular diastole. However, when it was 1.0 cm/s corresponded to lower coronary flow velocity at ventricular systole, particles with lower velocity (0 ≤ V ≤ 5 cm/s) were more prevalent around ACS-PR (p=0.035), whereas particles with higher velocity (10 ≤ V ≤ 20 cm/s) were more often detected in silent plaque ruptures (p=0.018).

    Conclusions: Three-dimensional IVUS revealed that coronary plaque rupture was a complex one with a wide variety of its stereoscopic configuration, leading to various patterns of the local coronary flow profile. A novel CFD analysis suggested that the local flow was more stagnant around ACS-provoked ruptures than in silent ones.

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  • Ryo Nishikawa, Masato Furuhashi, Mika Hori, Masatsune Ogura, Mariko Ha ...
    Type: Case Report
    Article ID: 58909
    Published: 2021
    [Advance publication] Released: February 27, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    A 56-year-old postmenopausal woman with out-of-hospital cardiac arrest caused by acute myocardial infraction was successfully resuscitated by intensive treatments and recovered without any neurological disability. She was diagnosed as having familial hypercholesterolemia (FH) based on a markedly elevated low-density lipoprotein cholesterol (LDL-C) level and family history of premature coronary artery disease. Genetic testing in her family members showed that a variant of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene (c.2004C>A, p.S668R), which had been previously reported as having uncertain significance, was associated with FH, indicating that the variant is a potential candidate for the FH phenotype. Next-generation sequencing analysis for the proband also showed that there was a heterozygous mutation of the ATP-binding cassette sub-family G member 5 (ABCG5) gene (c.1166G>A, R389H), which has been reported to increase LDL-C level and the risk of cardiovascular disease. She was also diagnosed as having type 1 CD36 deficiency based on a lack of myocardial uptake of 123 I-labeled 15-(p-iodophenyl)-3-R,S-methyl-pentadecanoic acid in scintigraphy and the absence of CD36 antigen in both monocytes and platelets in flow cytometry. She had a homozygous mutation of the CD36 gene (c.1126-5_1127delTTTAGAT), which occurs in a canonical splice site (acceptor) and is predicted to disrupt or distort the normal gene product. To our knowledge, this is the first report of a heterozygous FH phenotype caused by possibly oligogenic variants of the PCSK9 and ABCG5 genes complicated with type I CD36 deficiency caused by a novel homozygous mutation. Both FH phenotype and CD36 deficiency might have caused extensive atherosclerosis, leading to acute myocardial infarction in the present case.

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  • Jianwei Zhang, Yu Du, Chengping Hu, Yan Liu, Jinxing Liu, Ang Gao, Yin ...
    Type: Original Article
    Article ID: 61358
    Published: 2021
    [Advance publication] Released: February 27, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Aims: The associations between increased glycated albumin (GA) in the serum and diabetic complications and mortality have been revealed in the general population. However, less is known regarding the prognostic value of GA in patients diagnosed with acute coronary syndrome (ACS).

    Methods: In this study, all patients admitted for ACS who underwent a successful percutaneous coronary intervention (PCI) at our center from January 2018 to February 2019 were retrospectively examined. Clinical characteristics, laboratory results (e.g., serum GA levels), and procedural details were collected. The primary outcome included a composite of major adverse cardio-cerebral events (MACCE), such as death, myocardial infarction, stroke, and unplanned revascularization. The association between serum GA levels and clinical outcomes was tested in three multivariable models using Cox proportional hazard analysis. Subgroup analysis was performed in patients who were diagnosed with diabetes versus patients without diabetes.

    Results: A total of 1,806 ACS patients (mean age of 59.4 years; 77.8% were men; 44.9% were diagnosed with diabetes) were enrolled in this study, where the majority exhibited unstable angina (81.6%) and showed preserved left ventricular systolic function. Patients in the high GA level group were commonly female and were more likely to have metabolic disorders and to exhibit severe CAD (all p<0.05). MACCE occurred in 126 patients (7.0%) during a mean follow-up time of 17.2 months. The cumulative risk of MACCE at the 18-month follow-up visit significantly increased in a stepwise fashion along with increased GA levels (log-rank p=0.018) in the serum. The association between serum GA levels and MACCE was further determined after adjusting traditional risk factors and hemoglobin A1c (HbA1c) (GA, per 1% increase: hazard ratio [HR] 1.09, 95% confidence interval [CI] 1.06–1.13; GA, higher vs. lower tertial: HR 1.92, 95% CI 1.01–3.67). In a subgroup analysis, the prognostic role of serum GA only existed in diabetic patients, even when adjusting for traditional risk factors and HbA1c levels.

    Conclusions: Elevated GA levels in the serum were associated with poor intermediate-term outcomes in low-risk ACS patients who underwent PCI, especially in patients with preexisting diabetes.

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  • Daiji Nagayama, Atsuhito Saiki, Yasuhiro Watanabe, Takashi Yamaguchi, ...
    Type: Original Article
    Article ID: 62141
    Published: 2021
    [Advance publication] Released: February 27, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Aim: To clarify the mechanism by which pitavastatin reduced cardiovascular (CV) events more effectively than atorvastatin in the TOHO Lipid Intervention Trial Using Pitavastatin (TOHO-LIP), the changes in (Δ) non-heparinized serum level of lipoprotein lipase mass (LPL mass) during administration of the respective statins were investigated.

    Methods: From TOHO-LIP data, 223 hypercholesterolemic patients with any CV risks followed at Toho University Sakura Medical Center were analyzed. The patients were randomized to pitavastatin (2 mg/day) group (n=107) or atorvastatin (10 mg/day) group (n=116), and followed for 240 weeks. In this subgroup study, the primary and secondary end points were the same as those in TOHO-LIP, and 3-point major adverse cardiovascular events (3P-MACE) was added. The relationship between ΔLPL mass during the first year and the incidences of each end point was analyzed.

    Results: The lipid-lowering effect was not different between the two statins. Cumulative 240-week incidence of each end point was significantly lower in pitavastatin group (primary: 1.9% vs. 10.3%, secondary: 4.7% vs. 18.1%, 3P-MACE: 0.9% vs. 6.9%). Mean LPL mass (64.9 to 69.0 ng/mL) and eGFR (70.1 to 73.6 ml/min/1.73m2) increased in pitavastatin group, but not in atorvastatin group during the first year. Cox proportional-hazards model revealed that ΔLPL mass (1 ng/mL or 1SD) contributed to almost all end points.

    Conclusions: Pitavastatin administration reduced CV events more efficaciously than atorvastatin despite similar LDL cholesterol-lowering effect of the two statins. Increased LPL mass during the first year by pitavastatin treatment may be associated with this efficacy.

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  • Mitsuyoshi Takahara, Yoshimitsu Soga, Masahiko Fujihara, Daizo Kawasak ...
    Type: Original Article
    Article ID: 62356
    Published: 2021
    [Advance publication] Released: February 27, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Aim: This study aimed to reveal the mortality risk by age in patients undergoing femoropopliteal endovascular therapy for intermittent claudication, in comparison to the national age-specific standard value.

    Methods: We analyzed 2056 patients undergoing endovascular therapy for moderate to severe intermittent claudication between 2010 and 2018, performed at five cardiovascular centers in Japan. The 3-year mortality risk by age was compared with the data from year- and sex-matched Japanese citizens, which were obtained from Japan's national life table data. Clinical characteristics associated with age in the study patients were also explored.

    Results: The mean age was 73±9 years. The 3-year mortality risk was increased with age in the patient population, from 6.4% for patients aged <65 years to 21.2% for those aged ≥ 85 years. On the contrary, its risk ratio relative to the matched citizens of the same age was decreased with age; the relative risk ratio was 3.08 for patients aged <65 years (P=0.001) and 0.60 for those aged ≥ 85 years (P=0.016). Current smoking, body mass index ≥ 25 kg/m2, hyperlipidemia, diabetes mellitus, and dialysis dependence were inversely associated with age (all P<0.05).

    Conclusion: Mortality risk increased with age, but the risk ratio relative to the matched citizens decreased with age. Younger patients had a higher mortality risk relative to the matched citizens, whereas patients aged ≥ 85 years had a lower mortality risk relative to the matched citizens. Younger patients were more likely to accumulate cardiovascular risk factors.

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  • Jiali Sun, Guoqiang Liu, Dingyue Zhang, Zhigang Wu, Jingyao Liu, Wei ...
    Type: Original Article
    Article ID: 62448
    Published: 2021
    [Advance publication] Released: February 27, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Aims: This study aims to evaluate the differences in the characteristics of atherosclerotic plaques in the proximal, curved, and distal segments of the curved basilar artery (BA) through high-resolution magnetic resonance imaging(HR-MRI).

    Methods: The imaging and clinical data of 146 patients were retrospectively analyzed. On the basis of three-dimensional (3D) time -of -flight magnetic resonance angiography (3D-TOF-MRA), 51 patients with BA curvature were selected for the study. The BA plaque is divided into three groups: proximal, curved, and distal. Plaques were identified and analyzed according to spin echo acquisition imaging via T1-weighted 3D volumetric isotropic Tse acquisition (T1W-3D -VISTA), and compare the differences in clinical related factors and plaque characteristics between groups. Diffusion-weighted imaging (DWI) and/or T2WI identified brainstem infarction. The patients were divided into symptomatic and asymptomatic groups. The correlation between plaque location and symptoms was identified and analyzed.

    Results: Among 51 patients, a total of 376 plaques were detected. Plaques in the proximal and curved segments are more common than those in the distal segments. Proximal plaques are more likely to have intraplaque hemorrhage (P=0.002 <0.05). There was no significant difference in the distribution of criminal plaques and non-criminal plaques between each group (P=0.36 >0.05).

    Conclusion: Plaques in the proximal and curved segments of the BA are more common than those in the distal segments. The proximal plaque is more prone to intraplaque hemorrhage.

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  • Masato Nakamura, Junya Ako, Hidenori Arai, Atsushi Hirayama, Atsushi N ...
    Type: Original Article
    Article ID: 59543
    Published: 2021
    [Advance publication] Released: February 21, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Aim: The prevalence of atherosclerotic cardiovascular (CV) disease has risen in Japan due to increasing metabolic risk factors, including dyslipidemia. A positive linear correlation between low-density lipoprotein cholesterol (LDL-C) levels, incidence of CV events, and preventive effects of lipid-lowering therapy (LLT) is well established; however, data in Japan are limited. This analysis evaluated current lipid management practices and risk of recurrent CV events in Japanese post-acute coronary syndrome (ACS) patients.

    Methods: EXPLORE-J is a multicenter, 2-year observational study of hospitalized ACS patients in Japan.

    Results: At 2-year follow-up (n=1944, mean age 66 years, 80.3% male), the cumulative incidence of major adverse cardiovascular events (MACE; death associated with myocardial infarction/cerebrovascular accident [CVA] and other CV death, non-fatal ACS, and non-fatal CVA requiring hospitalization during the observation period) was 6.2%; respective incidences of CV death, non-fatal ACS, and CVA were 0.7%, 4.5%, and 1.7%. Statin, intensive statin, and ezetimibe were prescribed for 93.6%, 8.2%, and 3.9% at visit (V)1 (Day[D]1+14), and 92.3%, 10.5%, and 11.6% of patients at V5 (D730±30 days), respectively. Mean LDL-C was reduced from first post-ACS measurement (121.3 mg/dL) to V5 (79.8 mg/dL). A limited number of patients achieved LDL-C <70 mg/dL from V1–V5 (14.4%–34.6%); those with a greater LDL-C reduction by V1 had a lower probability of MACE, indicating the benefits of early LDL-C reduction post ACS.

    Conclusions: Guideline-recommended LDL-C target achievement post ACS in Japan is suboptimal, suggesting the need for LLT intensification. Additional analyses by risk stratification of the study population and the benefits of lipid management are planned.

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  • Kazushige Dobashi
    Type: Editorial
    Article ID: ED163
    Published: 2021
    [Advance publication] Released: February 21, 2021
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  • Masatsune Ogura
    Type: Editorial
    Article ID: ED164
    Published: 2021
    [Advance publication] Released: February 21, 2021
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  • Nahoko Kato-Kogoe, Shoichi Sakaguchi, Kuniyasu Kamiya, Michi Omori, Ya ...
    Type: Original Article
    Article ID: 60608
    Published: 2021
    [Advance publication] Released: February 19, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Aims: Oral bacteria have been reported to be associated with the pathogenesis of atherosclerosis; however, the relationship between the oral microbiota and atherosclerosis remains unclear. The present study aimed to investigate whether or not salivary microbiota of patients with atherosclerotic cardiovascular disease (ACVD) differs from that of subjects without ACVD, and to characterize the salivary microbiota of patients with ACVD.

    Methods: This study included 43 patients with ACVD and 86 age- and sex-matched non-ACVD individuals. 16S rRNA metagenomic analysis were performed using DNA isolated from the saliva samples of the participants. To select unique operational taxonomic unit (OTU) sets of ACVD, we conducted the random forest algorithm in machine learning, followed by confirmation via 10-fold cross-validation

    Results: There was no difference in richness or evenness between the ACVD and non-ACVD groups (alpha diversity; observed OTU index, p=0.503; Shannon's index, p=0.478). However, significant differences were found in the overall salivary microbiota structure (beta diversity; unweighted UniFrac distances, p=0.001; weighted UniFrac distances, p=0.001). The Actinobacteria phylum was highly abundant in patients with ACVD, while the Bacteroidetes phylum was less abundant. The random forest classifier identified 43 OTUs as an optimal marker set of ACVD. In a 10-fold cross validation using the validation data, an area under the curve (AUC) of 0.933 (95% CI, 0.855–1.000) was obtained.

    Conclusions: The salivary microbiota in patients with ACVD was distinct from that of non-ACVD individuals, indicating that the salivary microbiota may be related to ACVD.

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  • Yusuke Akiyama, Tetsuya Matoba, Shunsuke Katsuki, Susumu Takase, Soich ...
    Type: Original Article
    Article ID: 61366
    Published: 2021
    [Advance publication] Released: February 19, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Aims: Previous studies suggested that implantation with a 1st-generation DES was associated with coronary endothelial dysfunction, which was associated with Rho-kinase activation. Second-generation drug-eluting stents (DESs) may preserve coronary endothelial function in stented coronary arteries; however, because of methodological limitations, further study is needed to clarify the association between 2nd-generation DESs and coronary endothelial dysfunction.

    Methods: We retrospectively analysed the CuVIC trial database, where we identified 112 patients who underwent coronary stenting in the left coronary arteries with either a bare metal stent (BMS, n=53) or 2nd-generation DES (n=59). We compared vasomotions of target vessels with stents and non-target vessels without stents. Furthermore, we measured the Rho-kinase activation detected in mononucleocytes from aortic and coronary sinus blood.

    Results: ACh-induced vasoconstrictive responses of target vessels were not enhanced with a 2nd-generation DES (45±21% vs. 44±20%, P=0.56, paired t-test), but significantly enhanced in the coronary arteries with a BMS (50±18% vs. 42±20%, P=0.002). Rho-kinase activation did not differ between patients with a BMS and 2nd-generation DES. In the target vessels with a BMS, large late lumen loss and acute coronary syndrome (ACS) at the index percutaneous coronary intervention (PCI) were associated with ACh-induced enhanced coronary vasoconstrictive responses.

    Conclusions: Evaluation of ACh-induced vasomotion of target vessels comparing with non-target vessels revealed that 2nd-generation DESs were not associated with coronary endothelial dysfunction in target vessels, nor activation of Rho-kinase in the coronary sinus blood 6-8 months after stenting.

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  • Ho-Ming Su, Wen-Hsien Lee, Wei-Chung Tsai, Tzu-Chieh Lin, Ye-Hsu Lu, C ...
    Type: Original Article
    Article ID: 60806
    Published: 2021
    [Advance publication] Released: February 18, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Aim: Abnormal ankle-brachial index (ABI) is regarded as peripheral artery disease and can be used to predict cardiovascular (CV) outcomes. However, the usefulness of ABI for the prediction of CV outcome in patients with normal ABI is limited. Upstroke time per cardiac cycle (UTCC) is recently reported to be associated with mortality in patients with acute myocardial infarction and the elderly. Therefore, we aimed to evaluate UTCC, left ventricular ejection fraction (LVEF), brachial-ankle pulse wave velocity (baPWV), and ABI for the prediction of mortality in patients with normal ABI.

    Methods: Patients arranged for echocardiographic examinations were enrolled, and 1076 patients with normal ABI were included. ABI, baPWV, and UTCC were measured by an ABI-form device.

    Results: The median follow-up to mortality was 95 months. There were 88 CV and 244 all-cause deaths. After multivariate analysis, UTCC was associated with increased CV and all-cause mortality (P ≤ 0.004). Age, diabetes, heart failure, left ventricular hypertrophy, baPWV, and LVEF were also independent predictors of CV and all-cause mortality, but ABI was not. Furthermore, UTCC had a better additive predictive value than ABI, baPWV, and LVEF for CV mortality (P ≤ 0.012). It also had a better additive predictive value than ABI and LVEF for all-cause mortality (P ≤ 0.013).

    Conclusions: UTCC is an independent predictor for CV and all-cause mortality in patients with normal ABI. It also has a better additive predictive value of CV and all-cause mortality than ABI and LVEF. Therefore, UTCC is a simple, novel, and useful parameter for identifying high-risk patients with normal ABI.

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  • Haruka Chichibu, Kazumasa Yamagishi, Rie Kishida, Koutatsu Maruyama, M ...
    Type: Original Article
    Article ID: 61390
    Published: 2021
    [Advance publication] Released: February 18, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Aim: Seaweed contains soluble dietary fibers, potassium, and flavonoids and was recently reported to be inversely associated with the risk of coronary heart disease and mortality from stroke. However, epidemiological evidence on this issue has remained scarce.

    Methods: At the baseline survey of four Japanese communities between 1984 and 2000, we enrolled 6,169 men and women aged 40–79 years who had no history of cardiovascular disease. We assessed their seaweed intake using the data from a 24 h dietary recall survey and categorized the intake into four groups (0, 1–5.5, 5.5–15, and ≥ 15 g/day). We used sex-specific Cox proportional hazards models to examine the association between seaweed intake and risk of cardiovascular disease (stroke, stroke subtypes, and coronary heart disease).

    Results: During the 130,248 person-year follow-up, 523 cases of cardiovascular disease occurred: 369 cases of stroke and 154 cases of coronary heart disease. Seaweed intake levels were inversely associated with the risk of total stroke and cerebral infarction among men but not among women. Adjustment for cardiovascular risk factors did not change the associations: the hazard ratios (95% confidence intervals; P for trend) for the highest versus lowest categories of seaweed intake were 0.63 (0.42–0.94; 0.01) for total stroke and 0.59 (0.36–0.97; 0.03) for cerebral infarction. No associations were observed between seaweed intake and risks of intraparenchymal hemorrhage, subarachnoid hemorrhage, or coronary heart disease among men or women.

    Conclusions: We found an inverse association between seaweed intake and risk of total stroke, especially that from cerebral infarction, among Japanese men.

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  • Sono Toi, Yuka Shirai, Kentaro Ishizuka, Megumi Hosoya, Misa Seki, Eik ...
    Type: Original Article
    Article ID: 61895
    Published: 2021
    [Advance publication] Released: February 18, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Aims: This study aimed at clarifying the incidence of recurrent stroke and its etiology in patients with embolic stroke of undetermined source (ESUS) and other stroke subtypes in both the acute and chronic periods.

    Methods: A total of 645 patients who were admitted with acute ischemic stroke (IS) between March 2015 and August 2019 were enrolled. Among them, 511 patients with ESUS, cardioembolism (CE), large artery atherosclerosis (LAA), or small vessel disease (SVD) were analyzed in this study. After discharge, 391 patients who visited the outpatient clinic were followed up until August 2020. The outcome was stroke recurrence.

    Results: In the acute admission, recurrence rates were 7.6%, 8.1%, 18.8%, and 2.2% in patients with ESUS, CE, LAA, and SVD, respectively, and there were significant differences between the groups. The subtype of recurrence was almost identical to that of the index stroke. In the outpatient clinic, the annual recurrence rates were 4.4%, 4.3%, 6.0%, and 2.9% in ESUS, CE, LAA, and SVD, respectively, and no difference was observed. Subtypes of recurrence in outpatients with ESUS included ESUS, intracerebral hemorrhage (ICH), and SVD. Patients with ESUS and SVD had a higher risk of ICH during follow-up.

    Conclusions: Although the risk of recurrence was comparable between patients with ESUS and CE and intermediate between patients with LAA and SVD, in the acute admission unit, the risk in outpatients was similar among all subtypes. ESUS was the most recurrent stroke subtype in outpatients with ESUS. The risk of hemorrhagic stroke was significant in patients with SVD and ESUS.

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  • Naoko Higashino, Osamu Iida, Yosuke Hata, Mitsutoshi Asai, Masaharu Ma ...
    Type: Original Article
    Article ID: 60095
    Published: 2021
    [Advance publication] Released: February 14, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Aims: Hemodialysis vintage and serum phosphorus levels adversely affect outcomes in patients on hemodialysis. Whether these factors have a similar prognostic impact on patients who are on hemodialysis and have chronic limb-threatening ischemia (CLTI) has not been systematically studied. We aimed to explore the risk factors, including hemodialysis vintage and serum phosphorus levels, on clinical outcomes after endovascular therapy (EVT) in hemodialysis patients with CLTI.

    Methods: The current study rerospectively analyzed 374 hemodialysis patients with CLTI presenting with ischemic tissue loss (age: 72.3±9.0 years, male: 73.3%, diabetes mellitus: 68.2%, Rutherford 5: 75.9%, 6: 24.1%, WIfI stage 4: 50.0%) primarily treated with EVT between April 2007 and December 2016. The primary outcome measure was 1-year amputation-free survival (AFS), while the secondary outcome measure was 1-year wound healing. Predictors for each outcome were evaluated by Cox proportional hazards model.

    Results: Multivariate analysis significantly associated longer hemodialysis vintages with higher serum phosphorus levels (hazard ratio [HR], 0.599; 95% confidence interval [CI], 0.394-0.910; p=0.016) with 1-year AFS. Longer vintages for hemodialysis with higher serum phosphorus levels were marginally, but not significantly, associated with 1-year wound healing. (HR, 0.684; 95% CI, 0.467–1.000; p=0.050).

    Conclusion: Longer hemodialysis vintages with higher serum phosphorus levels adversely affect outcomes after EVT for hemodialysis patients with CLTI presenting with ischemic tissue loss.

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  • Yoshito Kadoya, Kan Zen, Osamu Iida, Yoshito Yamamoto, Daizo Kawasaki, ...
    Type: Original Article
    Article ID: 61150
    Published: 2021
    [Advance publication] Released: February 10, 2021
    JOURNALS OPEN ACCESS ADVANCE PUBLICATION

    Aim: The post-endovascular treatment outcomes of thrombotic lesions remain unclear. This study aimed to investigate the effects of thrombotic lesions on post-endovascular treatment outcomes in patients with non-acute aortoiliac total occlusions.

    Methods: This subanalysis of a multicenter prospective observational registry study included patients from 64 institutions in Japan between April 2014 and April 2016. A total of 346 patients (394 limbs; median age, 72 years), including 186 men, underwent endovascular treatment for non-acute aortoiliac total occlusions and were included. The patients were classified as having thrombotic or non-thrombotic lesions. The primary (1-year primary patency rate) and secondary (1-year overall survival rate) endpoints were evaluated.

    Results: Thrombotic lesions were identified in 18.5% (64/346) of the patients. The 1-year primary patency (85.9% versus 95.4%, log-rank p<.001) and overall survival (90.6% versus 97.9%, log-rank p=.003) rates were significantly lower in the thrombotic group than in the non-thrombotic group. Thrombotic lesions had significant effects on the post-endovascular treatment outcomes, with adjusted hazard ratios of 3.91 (95% confidence interval, 1.64–9.34, p=.002) for primary patency and 4.93 (95% confidence interval, 1.59–15.3, p=.006) for all-cause mortality.

    Conclusions: Thrombotic lesions were associated with 1-year restenosis and all-cause mortality after endovascular treatment for non-acute aortoiliac total occlusions. Endovascular treatment strategies should be carefully planned for patients with thrombotic lesions.

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