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.

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.

Aims: Although chronic kidney disease is recognized as an independent risk factor for cerebrovascular disease, its association with hemorrhagic and ischemic stroke remains controversial.

Methods: We conducted a retrospective cohort study using the National Health Insurance Service-National Sample Cohort, which is representative of the Korean population. A total of 195,772 Koreans who were not diagnosed with stroke before 2009 were included in this study from 2009 to 2013. The eGFR was divided into six categories (≥ 90, 75–89, 60–74, 45–59, 30–44, ＜30 mL/min/1.73 m²). The Kaplan–Meier plot was illustrated to compare the incidence of stroke. Cox proportional hazard model was used to estimate the hazard ratio (HR) of eGFR for risk of ischemic and hemorrhagic stroke by sex.

Results: During an average of 4.36 years of follow-up period, 2,236 and 668 people were diagnosed with newly ischemic and hemorrhagic stroke, respectively. Age-adjusted incidence rate for ischemic stroke among people with eGFR ＜45 mL/min/1.73 m² was higher than those with eGFR ≥ 90 mL/min/1.73 m², whereas that for hemorrhagic stroke among people with eGFR ≥ 90 mL/min/1.73 m² was higher than those with eGFR ＜45 mL/min/1.73 m². After adjusting for multiple covariates, the adjusted HR for ischemic stroke increased with decreasing eGFR in men (p for trend ＜0.001), but not in women (p for trend=0.48). On the other hand, there was no significant relationship between eGFR and risk of hemorrhagic stroke in both men and women.

Conclusions: Reduced glomerular filtration rate less than 45 mL/min/1.73 m² was associated with an increased risk of ischemic stroke, especially in men.

Aims: Smoking is a major risk factor for cardiovascular disease (CVD), a leading cause of death and disability. Other CVD risk factors include age, gender, hypertension, diabetes, increased low-density lipoprotein cholesterol (LDL-C) and decreased high-density lipoprotein cholesterol (HDL-C). Our goal was to assess relationships between smoking status and CVD risk factors, with a focus on direct LDL-C, HDL-C, triglycerides (TG) and small dense LDL-C (sdLDL-C).

Methods: A total of 34,497 Japanese men and women, mean age 51 years, had their CVD risk factors including fasting serum total cholesterol, TG, HDL-C, sdLDL-C, and direct LDL-C assessed. One-way ANOVA and multiple linear regression analyses were carried to assess the interrelationships of these parameters with smoking.

Results: In both men and women, current smokers had significantly (p＜0.001) higher median TG (+19.6%, +16.9%) and sdLDL-C levels (+12.7%, +4.2%) levels, and significantly (p＜0.001) lower HDL-C levels (-7.3%, -4.3%) than non-smokers. They were also significantly (p＜0.05) more likely to have TG values ＞150 mg/dL (+56.8%, +116.3%), sdLDL-C ＞40.1 mg/dL (+28.8%, +44.9%), and HDL-C ＜40 mg/dL (+89.8%, +114.3%). Ex-smokers generally had lipid values that were intermediate between non-smokers and current smokers. Multivariate analysis confirmed the significance of these relationships.

Conclusion: Our data indicate that current cigarette smoking is associated with increased TG and sdLDL-C levels, as well as decreased HDL-C levels. Furthermore, smoking effect on lipid profiles remain after cessation. These data provide further justification for smoking cessation.

Aim: The predictors of restenosis after endovascular therapy (EVT) with paclitaxel drug-coated balloons (DCBs) have not been clearly established. The present study aimed to investigate the association of post-procedural dissection, as evaluated using intravascular ultrasound (IVUS), with the risk of restenosis following femoropopliteal EVT with paclitaxel DCBs.

Methods: In the present single-center retrospective study, 60 de novo femoropopliteal lesions (44 patients) that underwent EVT with DCBs, without bail-out stenting, were enrolled. The primary outcome was 1-year primary patency. Risk factors for restenosis were evaluated using a Cox proportional hazards regression model and random survival forest analysis.

Results: The 1-year primary patency rate was 57.2% [95% confidence interval, 45%–72%]. IVUS-evaluated post-procedural dissection was significantly associated with the risk of restenosis (P=0.002), with the best cutoff point of 64º [range, 39º–83º]. The random survival forest analysis showed that the variable importance measure of IVUS-evaluated dissection was significantly lower than that of the reference vessel diameter (P＜0.001), not different from that of the lesion length (P=0.41), and significantly higher than that of any other clinical feature (all P＜0.05).

Conclusion: IVUS-evaluated post-procedural dissection was associated with 1-year restenosis following femoropopliteal EVT with DCB.

Aims: Volume elastic modulus (V_E), an index of arterial elasticity, and arterial diameter of the brachial artery can be automatically measured by a newly developed oscillometric device. We investigated the associations of V_E with flow-mediated vasodilation (FMD), an index of endothelium-dependent vasodilation, nitroglycerine-induced vasodilation (NID), an index of endothelium-independent vasodilation, and intima-media thickness (IMT) of the brachial artery and association of oscillometrically measured brachial artery diameter with ultrasonographically measured brachial artery diameter in patients with cardiovascular risk factors.

Methods: Oscillometric measurements of V_E and brachial artery diameter and ultrasound measurements of brachial artery diameter, FMD, NID, and IMT of the brachial artery were performed in 50 patients with cardiovascular risk factors.

Results: The mean values were 2.1±0.4 mmHg/% for V_E, 0.31±0.05 mm for brachial IMT, 4.48±0.70 mm for oscillometric brachial artery diameter, and 4.30±0.55 mm for ultrasound brachial artery diameter. V_E significantly correlated with brachial IMT (r=0.51, P＜0.001), whereas there was no significant correlation of V_E with FMD (r=-0.08, P=0.58) or NID (r=0.07, P=0.61). Multivariate analysis revealed that V_E was significantly associated with brachial IMT (β=0.33, P=0.04). Oscillometric brachial artery diameter significantly correlated with ultrasound brachial artery diameter (r=0.79, P＜0.001). The Bland-Altman plot showed good agreement between oscillometric brachial artery diameter and ultrasound brachial artery diameter (mean difference, -0.17 mm; limits of agreement, -1.03 mm to 0.69 mm).

Conclusions: In patients with cardiovascular risk factors, V_E may represent atherosclerotic structural alterations of the vascular wall but not vascular function. The accuracy of oscillometric measurement of brachial artery diameter is acceptable.

Aim:We established a method to evaluate the lipid concentrations, size and particle numbers (PNs) of lipoprotein subclasses by gel permeation chromatography (GP-HPLC). Nuclear magnetic resonance (NMR) is widely used to analyze these parameters of lipoprotein subclasses, but differences of the two methods are unknown. Current study compared the PNs of each lipoprotein subclass measured by GP-HPLC and NMR, and assessed the effect of a selective PPARα modulator, pemafibrate.

Methods: Lipoprotein profiles of 212 patients with dyslipidemia who participated in the phase 2 clinical trial of a selective PPARα modulator, pemafibrate, were analyzed by two methods, GP-HPLC and NMR, which were performed with LipoSEARCH (Skylight Biotech) and LipoProfile 3 (LabCorp), respectively. GP-HPLC evaluated the PNs of 18 subclasses, consisting of CM, VLDL1-5, LDL1-6, and HDL1-6. NMR evaluated the PNs of 9 subclasses, consisting of large VLDL & CM, medium VLDL, small VLDL, IDL, large LDL, small LDL, large HDL, medium HDL and small HDL.

Results: Three major classes, total CM&VLDL, total LDL and total HDL were obtained by grouping of corresponding subclasses in both methods and PNs of these classes analyzed by GP-HPLC were correlated positively with those by NMR. The correlation coefficients in total CM&VLDL, total LDL and total HDL between GP-HPLC and NMR was 0.658, 0.863 and 0.798 (all p＜0.0001), respectively. The PNs of total CM&VLDL, total LDL and total HDL analyzed by GP-HPLC was 249.5±51.7nM, 1,679±359 nM and 13,273±1,564 nM, respectively, while those by NMR was 124.6±41.8 nM, 1,514±386 nM and 31,161±4,839 nM, respectively. A marked difference in the PNs between the two methods was demonstrated especially in total HDL.

The number of apolipoprotein (Apo) B molecule per one ApoB-containing lipoprotein particle, total CM&VLDL plus total LDL, was 1.10±0.05 by GP-HPLC, while 1.32±0.18 by NMR. The number of ApoA-I per one HDL particle was 3.40±0.17 by GP-HPLC, but only 1.46±0.15 by NMR, much less than reported previously.

From the phase 2 clinical trial, randomizing 212 patients to pemafibrate 0.025-0.2 mg BID, fenofibrate 100 mg QD, or placebo groups, pemafibrate reduced the PNs of CM, large VLDL1-VLDL3 and medium VLDL4, but not small VLDL5 by GP-HPLC. It significantly decreased the PNs of smaller LDL and larger HDL particles, but increased those of larger LDL and smaller HDL particles. In contrast, NMR showed marked variations in the effect of pemafibrate on lipoprotein PNs, and no significant size-dependent changes.

Conclusions: GP-HPLC evaluates the lipoprotein PNs more accurately than NMR and can be used for assessing the effects of lipid-lowering drugs on lipoprotein subclasses.

Aim: To explore the predictive values of different small vessel disease (SVD) scores on functional recoveries and the clinical cerebrovascular events in mild intracerebral hemorrhage (ICH).

Methods: In this study, we enrolled conscious and mild ICH patients without surgery and further divided them into the cerebral amyloid angiopathy (CAA)-ICH group and hypertension (HTN)-ICH group. The severity of individual SVD markers, including lacunes, cerebral microbleeds (CMBs), enlarged perivascular spaces (EPVS), white matter hyperintensity (WMH), and cortical superficial siderosis (cSS), was evaluated. The original SVD score, modified SVD score, refined SVD score, and CAA-SVD score and the total number of SVD markers were further calculated. Functional recoveries were evaluated using the modified Rankin scale. Recurrences of stroke were defined as readmission to the hospital with a definite diagnosis of stroke.

Results: A total of 163 ICH patients (60 CAA-ICH and 103 HTN-ICH) were included in the study. The CAA-SVD score (OR=3.429; 95% confidence interval (CI)=1.518–7.748) had the best predictive effect on functional dependence in the CAA-ICH group, among which cSS severities probably played a vital role (OR=4.665; 95% CI=1.388–15.679). The total number of SVD markers [hazard ratio (HR)=3.765; 95% CI=1.467–9.663] can better identify stroke recurrences in CAA-ICH. In HTN-ICH, while the total number of SVD markers (HR=2.136; 95% CI=1.218–3.745) also demonstrated association with recurrent stroke, this effect seems to be related with the influence of lacunes (HR=5.064; 95% CI=1.697–15.116).

Conclusions: The CAA-SVD score and the total number of SVD markers might identify mild CAA-ICH patients with poor prognosis. However, it would be better to focus on lacunes rather than on the overall burden of SVD to predict recurrent strokes in HTN-ICH.